https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Jonathan+HurstProteopedia - User contributions [en]2026-09-12T15:41:39ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=GABA_receptor&diff=2508006GABA receptor2015-12-08T02:24:31Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine1/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent <scene name='71/716457/Trp1/1'>lysine and tryptophan residues</scene>, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2508005GABA receptor2015-12-08T02:24:06Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine1/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent <scene name='71/716457/Trp1/1'>lysine and tryptophan residues</scene>, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
<br />
== Proteopedia Page Contributors and Editors ==</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2508001GABA receptor2015-12-08T02:22:38Z<p>Jonathan Hurst: Sandbox1738 moved to GABAB Receptor</p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine1/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent <scene name='71/716457/Trp1/1'>lysine and tryptophan residues</scene>, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498129GABA receptor2015-11-17T05:17:13Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine1/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent <scene name='71/716457/Trp1/1'>lysine and tryptophan residues</scene>, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498127GABA receptor2015-11-17T05:14:38Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine1/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent <scene name='71/716457/Tyrosine/2'>lysine and tryptophan residues</scene>, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498126GABA receptor2015-11-17T05:11:31Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosinep/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent <scene name='71/716457/Tyrosine/2'>lysine and tryptophan residues</scene>, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498124GABA receptor2015-11-17T05:09:16Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine3/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent <scene name='71/716457/Tyrosine/2'>lysine and tryptophan residues</scene>, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498122GABA receptor2015-11-17T05:08:52Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine3/1'>TextToBeDisplayed</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent <scene name='71/716457/Tyrosine/2'>lysine and tryptophan residues</scene>, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498120GABA receptor2015-11-17T05:03:02Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013). Lastly, the tyrosine residues, with adjacent lysine and tryptophan residues, are able to participate in hydrophobic interactions that contribute to the heterodimer's stability (Geng, 2013). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498110GABA receptor2015-11-17T04:46:08Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013).<br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3) (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498105GABA receptor2015-11-17T04:41:43Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Geng, 2013). These tyrosine residues are effective in linking the heterodimer as the base-stacking interactions and hydrogen bonding stabilize the quaternary structure (Geng, 2013).<br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498092GABA receptor2015-11-17T04:26:50Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via the <scene name='71/716457/Tyrosine/1'>tyrosine residues</scene> on the intracellular C-termini to form the heterodimer GABAB receptor (Gumerov, 2015). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
(2015). GABAB Receptors. Sigma Alrdrich Co. LLC. Retrieved from: http://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook/non-peptide-receptors-synthesis-and-metabolism/gabab-receptors.html<br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498066GABA receptor2015-11-17T03:58:44Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (Gumerov, 2015). <br />
<br />
The GABAB receptor exists in the <scene name='71/716457/Gabab_rest/1'>resting state</scene> (PDB: 4MQE) and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
(2015). GABAB Receptors. Sigma Alrdrich Co. LLC. Retrieved from: http://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook/non-peptide-receptors-synthesis-and-metabolism/gabab-receptors.html<br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498062GABA receptor2015-11-17T03:57:03Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='GABAB Receptor' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The <scene name='71/716457/Gabab_rest/1'>GABAB receptor</scene> functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green) (PBD: 4MQE). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (Gumerov, 2015). <br />
<br />
The GABAB receptor exists in the resting state and the <scene name='71/716457/Active_state/1'>active state</scene> (PDB: 4MS3)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is noted by the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
(2015). GABAB Receptors. Sigma Alrdrich Co. LLC. Retrieved from: http://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook/non-peptide-receptors-synthesis-and-metabolism/gabab-receptors.html<br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498054GABA receptor2015-11-17T03:54:03Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The <scene name='71/716457/Gabab_rest/1'>GABAB receptor</scene> functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green) (PBD: 4MQE). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (Gumerov, 2015). <br />
<br />
The GABAB receptor exists in the resting state and the <scene name='71/716457/Active_state/1'>active state</scene> (Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013) (see below). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene> (PDB: 4MS3), located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 in the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
(2015). GABAB Receptors. Sigma Alrdrich Co. LLC. Retrieved from: http://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook/non-peptide-receptors-synthesis-and-metabolism/gabab-receptors.html<br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498050GABA receptor2015-11-17T03:50:29Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The <scene name='71/716457/Gabab_rest/1'>GABAB receptor</scene> functions as a heterodimer of two subunits, GABAB1 (grey) and GABAB2 (green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (Gumerov, 2015). <br />
<br />
The GABAB receptor exists in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013) (see below). Additionally, it was found that the agonist (i.e. GABA) is bound to the <scene name='71/716457/Active_site_iwith_gaba_bound/1'>active site</scene> (PDB: 4MS3), located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 in the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
(2015). GABAB Receptors. Sigma Alrdrich Co. LLC. Retrieved from: http://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook/non-peptide-receptors-synthesis-and-metabolism/gabab-receptors.html<br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498045GABA receptor2015-11-17T03:44:03Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (Gumerov, 2015). <br />
<scene name='71/716457/Sushi_domains/1'>TextToBeDisplayed</scene><br />
The GABAB receptor exists in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013) (see below). Additionally, it was found that the agonist is bound to the <scene name='71/716457/Active_site_of_gaba-b/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 in the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<scene name='71/716457/Active_site_iwith_gaba_bound/1'>Active site with GABA bound</scene><br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
(2015). GABAB Receptors. Sigma Alrdrich Co. LLC. Retrieved from: http://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook/non-peptide-receptors-synthesis-and-metabolism/gabab-receptors.html<br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2498040GABA receptor2015-11-17T03:36:54Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (Gumerov, 2015). <br />
<br />
The GABAB receptor exists in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013) (see below). Additionally, it was found that the agonist is bound to the <scene name='71/716457/Active_site_of_gaba-b/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 in the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<scene name='71/716457/Active_site_iwith_gaba_bound/1'>Active site with GABA bound</scene><br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
(2015). GABAB Receptors. Sigma Alrdrich Co. LLC. Retrieved from: http://www.sigmaaldrich.com/technical-documents/articles/biology/rbi-handbook/non-peptide-receptors-synthesis-and-metabolism/gabab-receptors.html<br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497949GABA receptor2015-11-17T02:08:03Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (Gumerov, 2015). <br />
<br />
The GABAB receptor exists in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013) (see below). Additionally, it was found that the agonist is bound to the <scene name='71/716457/Active_site_of_gaba-b/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 in the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrome, 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Gumerov, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome, 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Filip, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497936GABA receptor2015-11-17T01:54:40Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (GABA B Receptors, 2015). <br />
<br />
The GABAB receptor exists in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013) (see below). Additionally, it was found that the agonist is bound to the <scene name='71/716457/Active_site_of_gaba-b/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 in the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (GABA B Receptors, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497934GABA receptor2015-11-17T01:52:38Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (GABA B Receptors, 2015). <br />
<br />
The GABAB receptor exists in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes (Geng, 2013) (see below). Additionally, it was found that the agonist is bound to the <scene name='71/716457/Active_site_of_gaba-b/1'>active site</scene>, located at the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 in the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (GABA B Receptors, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497749GABA receptor2015-11-16T03:26:16Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA (i.e. gamma-aminobutyric acid) is the primary inhibitory neurotransmitter of the vertebrate central nervous system (Kerr, 1995). GABA can bind one of two different receptor proteins, each using a discrete mechanism to elicit a cellular response. Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
Ionotropic and metabotropic are the two major classes of GABA receptors abundant throughout neuronal cells (Cryan, 2005). Metabotropic GABAB receptors induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished through interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together in the endoplasmic reticulum as GABAB2 connects to GABAB1 via their intracellular C-termini to form the heterodimer GABAB receptor (GABA B Receptors, 2015). <br />
<br />
The GABAB receptor exists in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Using the GABAB crystal structures, Geng et al. found that both subunits exist in open conformations while at rest. Upon binding with the agonist the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 in the visible reduction in space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABAB receptors have been found to provide an inhibitory function through coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in hyperpolarization of the neuronal membrane due to the highly negative Nernst value of potassium common to cerebrospinal fluid. Hyperpolarization of the neuronal membrane is the decrease in the neuron’s membrane potential away from threshold which results in the inhibition of GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Besides interacting with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is thought to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are the target of a number of treatments in the clinical setting of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene locus on chromosome 6 is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (GABA B Receptors, 2015). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addiction). The GABAB receptor has been found to play a crucial role in mediating behavioral and molecular effects of drug abuse and could be used as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists of GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
<references/><br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
<br />
Citrome, L., Javitt, D., Kantrowitz, J. (2009). GABAB Receptors, Schizophrenia and Sleep Dysfunction. CNS Drugs, 23(8), 681-691.<br />
<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
<br />
Filip, M., Frankowska, M., et al., (2015). GABAB receptors as a therapuetic strategy in substance use disorders: Focus on positive allosteric modulators. Neuropharmacology. (38), 36-47. <br />
<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
<br />
Gumerov, V., Hegyi, H. (2015). MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1].Gumerov and Heygl Biology Direct. 10:59, 1-15.<br />
<br />
Kerr, D. I. B., and J. Ong. "Clinical Potential of GABA B Receptor Modulators." CNS Drug Reviews. 11.3 (2005): 317-334.<br />
<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.</div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497509GABA receptor2015-11-13T05:30:19Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor that induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished using interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). <br />
<br />
The GABAB receptor exists in two different forms - in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 as one may notice the reduction in the space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium common to cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497508GABA receptor2015-11-13T05:28:45Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor that induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished using interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 as one may notice the reduction in the space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium common to cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for disorders such as multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497507GABA receptor2015-11-13T05:26:10Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor that induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - gray; GABAB2 - green). Heterodimerization is accomplished using interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 as one may notice the reduction in the space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium common to cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497506GABA receptor2015-11-13T05:22:39Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in an inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor that induce a change in membrane potential through the action of a second messenger pathway (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2 (Figure 1: GABAB1 - grey; GABAB2 - green). Heterodimerization is accomplished using interactions of the coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit are key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state (Figure 1) and the active state (Figure 2)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). This conformation change is highlighted in Figures 1 and 2 as one may notice the reduction in the space between GABAB subunits upon binding with GABA. <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005).Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004).<br />
<br />
It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004).<br />
Do we need this section???<br />
<br />
This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497505GABA receptor2015-11-13T04:27:30Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Figure 1. Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in the inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit is key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state (i.e. unbound state) and the active state (i.e. bound state)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Figure 2. Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of the Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the GABA neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor in order to control and slow the inhibitory postsynaptic potentials as the GABAA receptor activation causes a more transient inhibitory signal (Cryan, 2005).Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004).<br />
<br />
It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004).<br />
Do we need this section???<br />
<br />
This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). <br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addiction (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the expression of the GABAB1 receptor was found to have a high amount of methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals (i.e. neuronal terminals that secrete dopamine) have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment of substance use disorder (i.e. drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497504GABA receptor2015-11-13T04:12:42Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in the inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit is key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). The two GABAB subunits link together as GABAB2 connects to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state (i.e. unbound state) and the active state (i.e. bound state)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addition (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the GABAB1 receptor was found to have a high number of differentially methylated CpGs, or hyper methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment substance use disorder (drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497485GABA receptor2015-11-12T18:34:10Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). Upon binding with GABA, GABAB receptors utilize a second messenger amplification pathway that ultimately results in the inhibitory signal for neuronal transmission. This pathway for signal transmission differs from GABAA receptors, which are considered ligand-gated ion channels as the binding of GABA results in the opening of ion channels leading to the inhibition of a neuronal signal. <br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). Additionally, there are two GABAB1 isoforms that differ at the N-termini where there are two sushi domains (Cryan, 2005). These sushi domains on the GABAB1 subunit is key to the receptor's interaction with other proteins as well as axonal signaling (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state (i.e. unbound state) and the active state (i.e. bound state)(Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes(Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). <br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addition (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the GABAB1 receptor was found to have a high number of differentially methylated CpGs, or hyper methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment substance use disorder (drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497361GABA receptor2015-11-10T17:56:25Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).<br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
GABAB receptors are targeted for a number of treatments in the clinical setting of neurodegenerative and pathophysiolocial disorders including epilepsy, spasticity, chronic pain, anxiety, depression, schizophrenia, cognitive function, gastro-esophageal reflux and drug dependence and addition (Kerr 2005).<br />
<br />
There is increasing evidence that links schizophrenia directly to GABAB receptor deficits. GABBR1, the gene associated with the GABAB1 receptor was found to have a high number of differentially methylated CpGs, or hyper methylation in receptors tested for patients with schizophrenia (Citrine et al. 2009). The receptor 1 gene is on chromosome 6 where the locus is susceptible for multiple sclerosis, epilepsy, and schizophrenia (Sigma Aldrich). Presynaptic dopaminergic terminals have GABAB receptors that are involved in the release of dopamine along with modulation of glutaminergic regulation of dopamine (Citrome et al. 2009). <br />
<br />
A possible therapeutic approach utilizing GABAB receptors would be for the treatment substance use disorder (drug addition). Since the GABAB receptor plays a crucial role in mediating behavioral and molecular effects of drug abuse, the GABAB receptor can be utilized as a potential anti-addictive therapeutic strategy (Flip et. al, 2015). Agonists at GABAB receptors can promote abstinence or decrease and control the reinforcing effects of drugs on the mind (Kerr 2005).<br />
<br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497325GABA receptor2015-11-09T19:36:35Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).<br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
[[Image:GABAB receptor 1.gif|right|350px]]<br />
</StructureSection><br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497323GABA receptor2015-11-09T19:16:23Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the unbound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).<br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Display of the GABAB receptor while in the bound state (Geng, 2013)' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
<br />
</StructureSection><br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497322GABA receptor2015-11-09T19:14:07Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest (see above). Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013) (see below). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).<br />
<br />
== Function ==<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
<br />
</StructureSection><br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497316GABA receptor2015-11-09T19:07:39Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).<br />
<br />
== Function ==<br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
<br />
</StructureSection><br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497314GABA receptor2015-11-09T19:06:39Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
<br />
<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).<br />
<br />
== Function ==<br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497312GABA receptor2015-11-09T19:06:18Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).<br />
<br />
== Function ==<br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497311GABA receptor2015-11-09T19:04:47Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
There are two major classes of GABA receptors abundant throughout neuronal cell types, ionotropic and metabotropic (Cryan, 2005). Metabotropic GABAB receptors are a specific division of the GABA receptor (Kerr, 1995). The GABAB receptor functions as a heterodimer of two subunits, GABAB1 and GABAB2. Heterodimerization is accomplished using coiled-coil motifs within the C-termini and interactions between the transmembrane and extracellular domains (Cryan, 2005). GABAB1, a seven-transmembrane spanning protein receptor was identified first using an expression cloning technique using radiolabeled iodinated receptor ligands. The GABAB1 subunit has a molecular weight of 130 kDa. It is not expressed on the cell surface without the help of the seven transmembrane spanning motif GABAB2. GABAB2 links to GABAB1 at the endoplasmic reticulum via their intracellular C-terminus to form the heterodimer GABAB receptor (Sigma Aldrich). The GABAB receptor exists in two different forms - in the resting state and the active state which has the agonist bound (Geng, 2013). Geng et. al. has found, using the GABAB crystal structures, that both subunits exist in open conformations while at rest. Upon binding with the agonist, the GABAB1 subunit closes via agonist-induced receptor activation (Geng, 2013). Additionally, it was found that the agonist is bound in the interdomain crevice of the GABAB1 subunit due to an overlap of amino acid residues (Geng, 2013). There are two GABAB1 isoforms that differ at the N-termini where there are two sushi motifs (Cryan, 2005).<br />
<br />
== Function ==<br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<br />
Bettler, B., Kaupmann, K., Mosbacher, J., & Gassmann, M. (2004). Molecular structure and physiological functions of GABAB receptors. Physiological reviews, 84(3), 835-867.<br />
Cryan, J.F., Kaupman, K. (2005). Don’t worry ‘B’ happy!: a role for GABAB receptors in anxiety and depression. Trends in Pharmacological Sciences, 26(1), 36-43.<br />
Geng, Y., Bush, M., Mosyak, L., Wang, F., & Fan, Q. R. (2013). Structural mechanism of ligand activation in human GABAB receptor. Nature, 504(7479), 254-259.<br />
Kerr, D. I. B., and J. Ong. "Gaba B receptors." Pharmacology & therapeutics. 67.2 (1995): 187-246.<br />
Lloyd, K. G., Bossi, L., Morselli, P. L., Munari, C., Rougier, M., & Loiseau, H. (1985). Alterations of GABA-mediated synaptic transmission in human epilepsy.Advances in neurology, 44, 1033-1044.<br />
<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497309GABA receptor2015-11-09T19:03:10Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
Anything in this section will appear adjacent to the 3D structure and will be scrollable.<br />
<br />
GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.<br />
<br />
== Structure ==<br />
<br />
== Function ==<br />
It has been found that GABAB receptors provide an inhibitory function through the coupling to G-proteins and the recruitment of second messengers (Bettler, 2004). Presynaptic GABAB receptors effectively repress the influx of calcium ions (Ca2+) via the inhibition of voltage gated Ca2+ channels through the activation of Gβγ subunits (Bettler, 2004). Postsynaptic GABAB receptors then activate the opening of potassium ion (K+) channels, again through the activation of Gβγ subunits (Bettler, 2004). The efflux of potassium ions results in the hyperpolarization of the neuronal membrane due to the greatly negative Nernst value of potassium in cerebrospinal fluid. This hyperpolarization of the neuronal membrane causes the neuron’s membrane potential to move away from threshold, thus inhibiting the gaba neuronal function (Bettler, 2004). This functions in opposition of the GABAA receptor to control and slow the inhibitory postsynaptic potentials (Cryan, 2005). Aside from the interaction with ion channels, GABAB receptors also inhibit adenylyl cyclase through the Giα/Goα subunits and activate adenylyl cyclase through Gβγ subunits (Bettler, 2004). It has been found that the Giα/Goα subunits inhibit adenylyl cyclase types I, III, V, and VI (Bettler, 2004). Additionally, the Gβγ subunits stimulates adenylyl cyclase types II, IV, and VII (Bettler, 2004). This control of adenylyl cyclase is expected to control neuronal function for a longer period of time compared to the control via ion channels (Geng, 2013). The GABAB1 sushi domains are axonal trafficking signals that help to localize the receptors to glutmatergic terminals (Cryan 2005).<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497306GABA receptor2015-11-09T19:00:10Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
Anything in this section will appear adjacent to the 3D structure and will be scrollable.<br />
<br />
<br />
This is a default text for your page '''Sandbox1738'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Structure ==<br />
'GABA receptors are proteins utilized for the primary inhibitory neurotransmitter in vertebrate central nervous systems, gamma-aminobutyric acid or GABA (Kerr, 1995). GABA has been found to be formed using the synthesizing enzyme, L-glutamic acid carboxylase, or GAD (Lloyd, 1983). Additionally, GABA has found to be synthesized via the excitatory neurotransmitter glutamate. GABA receptors regulate synaptic transmission via the opening of ion channels, causing membrane hyperpolarization and the inhibition of further signal transmission.'<br />
<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497304GABA receptor2015-11-09T18:49:17Z<p>Jonathan Hurst: </p>
<hr />
<div><Structure load='4MQE' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<Structure load='4MS3' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
Anything in this section will appear adjacent to the 3D structure and will be scrollable.<br />
<br />
<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Sandbox1738'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Jonathan Hursthttps://proteopedia.org/index.php?title=GABA_receptor&diff=2497084GABA receptor2015-11-04T00:56:38Z<p>Jonathan Hurst: New page: ==Your Heading Here (maybe something like 'Structure')== GABAb Receptor <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> This is a defa...</p>
<hr />
<div>==Your Heading Here (maybe something like 'Structure')== GABAb Receptor<br />
<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Sandbox1738'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Jonathan Hurst