GABA receptor: Difference between revisions

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== Structure ==

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~~).

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 (GABA B Receptors, 2015).

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.

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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).

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).

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 (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).

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).

GABA receptor: Difference between revisions

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@@ Line 3: / Line 3: @@
 == Structure ==
-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).
+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 (GABA B Receptors, 2015).
 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.
@@ Line 15: / Line 15: @@
 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).
-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).
+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 (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).
 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).