Sandbox 173: Difference between revisions

Line 5:

===G Protein-Coupled Receptors===

Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signalling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref>Article 20</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref>Article 12</ref>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref>Article 20</ref>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case transducin, which interacts with the cytoplasmic loops of the receptor<ref>Article 10</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref>Article 20</ref>.

Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signalling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref>Article 20</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref>Article 12</ref>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref>Article 20</ref>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case [http://en.wikipedia.org/wiki/Transducin transducin], which interacts with the cytoplasmic loops of the receptor<ref>Article 10</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref>Article 20</ref>.

Line 26:

===Retinal Chromophore of Rhodospin===

Rhodopsin consists of an opsin apoprotein and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in yellow) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref>Article 19</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref>Article 12</ref>. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in green) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore <ref>Article 4</ref>. The protonated Schiff base of rhodopsin is stabilized through <scene name='Sandbox_173/Glu113/1'>Glutamine 113</scene> residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state<ref>Article 20</ref>.

Rhodopsin consists of an opsin [http://en.wikipedia.org/wiki/Apoprotein apoprotein] and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in yellow) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref>Article 19</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref>Article 12</ref>. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in green) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore <ref>Article 4</ref>. The protonated Schiff base of rhodopsin is stabilized through <scene name='Sandbox_173/Glu113/1'>Glutamine 113</scene> residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state<ref>Article 20</ref>.

As this ligand is bound in the 12-s-''trans'' conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation<ref>Article 2</ref>. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation <ref>Original article</ref>.

Line 55:

====Signalling Cascade and Polarization of the Cell Membrane====

The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref>Article 6</ref>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates cGMP-specific phosphodiesterase by binding and removing its inhibitory subunit<ref>Textbook</ref>.

The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref>Article 6</ref>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates [http://en.wikipedia.org/wiki/CGMP-specific_phosphodiesterase_type_5 cGMP-specific phosphodiesterase] by binding and removing its inhibitory subunit<ref>Textbook</ref>.

The cGMP phosphodiesterase is an integral protein of the retina with its active site on the cytoplasmic side of the disk. Its inhibitory subunit tightly binds to it in the dark and suppresses its activity. The now activated phosphodiesterase degrades many molecules of cGMP, efficiently decreasing the concentration of cGMP <ref>Textbook</ref>. This results in the closing of the cGMP-gated cation channels in the plasma membrane of the outer segment. The cell hyperpolarizes due to the decrease in the influx of sodium and calcium ions, which results in the decrease of the release of glutamate into the synaptic cleft. This electric signal of this hyperpolarization is sent to the brain through ranks of interconnecting neurons and then through the optic nerve<ref>Article 6</ref>.

Line 61:

====Recovery of the Pre-stimulus State====

In the event of a decrease in light intensity, GTP is hydrolyzed and the α-subunit of transducin reassociates with the βγ subunits, releasing the inhibitory subunit of phosphodiesterase. This subunit reassociates with phosphodiesterase and inhibits its activity<ref>Textbook</ref>.

The concentration of cGMP is returned to the “dark” state by the conversion of GTP to cGMP by guanylyl cyclase, activated through the efflux of calcium ions through the sodium/calcium ion exchanger. The reduction in the concentration of calcium ions also inhibits phosphodiesterase activity. Both actions reopen the cation channels and restore the system to pre-stimulus state<ref>Textbook</ref>.

The concentration of cGMP is returned to the “dark” state by the conversion of GTP to cGMP by [http://en.wikipedia.org/wiki/Guanylate_cyclase guanylyl cyclase], activated through the efflux of calcium ions through the sodium/calcium ion exchanger. The reduction in the concentration of calcium ions also inhibits phosphodiesterase activity. Both actions reopen the cation channels and restore the system to pre-stimulus state<ref>Textbook</ref>.

====Phosphorylation and Deactivation of Rhodopsin====

Rhodopsin kinase phosphorylates rhodopsin and arrestin binds to the phosphorylated domain of rhodopsin, preventing further signal transduction from Metarhodopsin II of activated rhodopsin and transducin<ref>Article 3</ref>. It phosphorylates both Metarhodopsin II and cone opsins. The majority of the phosphorylation sites are in the cytoplasmic C-terminal region of rhodopsin with seven hydroxy-amino acids. The most favoured amino acids are <scene name='Sandbox_173/Phosphorylated_sites/1'>Serine 338, Serine 343, Serine 334, Threonine 335 and Threonine 336</scene><ref>Article 7</ref>, and these residues form an arrangement in rhodopsin that ~~does~~ not appear to be exposed to the solvent. Interactions with the C-terminal tail and a portion of the Cytoplasmic loop 3 appear to be broken for the phosphorylation of the hydroxyl groups<ref>Article 9</ref>. For the next cycle of activation of rhodopsin, rhodopsin has to be dephosphorylated, and have the all-''trans'' retinal replaced with the 11-''cis'' retinal<ref>Article 19</ref>.

[http://en.wikipedia.org/wiki/Rhodopsin_kinase Rhodopsin kinase] phosphorylates rhodopsin and [http://en.wikipedia.org/wiki/Arrestin arrestin] binds to the phosphorylated domain of rhodopsin, preventing further signal transduction from Metarhodopsin II of activated rhodopsin and transducin<ref>Article 3</ref>. It phosphorylates both Metarhodopsin II and cone opsins. The majority of the phosphorylation sites are in the cytoplasmic C-terminal region of rhodopsin with seven hydroxy-amino acids. The most favoured amino acids are <scene name='Sandbox_173/Phosphorylated_sites/1'>Serine 338, Serine 343, Serine 334, Threonine 335 and Threonine 336</scene><ref>Article 7</ref>, and these residues form an arrangement in rhodopsin that do not appear to be exposed to the solvent. Interactions with the C-terminal tail and a portion of the Cytoplasmic loop 3 appear to be broken for the phosphorylation of the hydroxyl groups<ref>Article 9</ref>. For the next cycle of activation of rhodopsin, rhodopsin has to be dephosphorylated, and have the all-''trans'' retinal replaced with the 11-''cis'' retinal<ref>Article 19</ref>.

Altogether, the different states of rhodopsin which include the short-lived, photo-rhodopsin, batho-rhodopsin, and lumi-rhodopsin, and longer-lived meta-rhodopsins give information about the structural status of the molecule during activation<ref>Article 9</ref>.

Line 75:

===Activity===

~~Opsin is the [http://en.wikipedia.org/wiki/Apoprotein apoprotein] component~~ of ~~rhodopsin. Its ability~~ to activate transducin is modulated by both 11-''cis'' retinal and the all-''trans'' retinal; the 11-''cis'' retinal reduces its activity while the all-''trans'' retinal enhances it through non-covalent interactions <ref>Article Opsin 1</ref>. This may give insight on the ability of all-''trans'' retinal, in combination with opsin, to alter the photoreceptor sensitivities<ref>Article Opsin 1</ref>.

The ability of opsin to activate transducin is modulated by both 11-''cis'' retinal and the all-''trans'' retinal; the 11-''cis'' retinal reduces its activity while the all-''trans'' retinal enhances it through non-covalent interactions <ref>Article Opsin 1</ref>. This may give insight on the ability of all-''trans'' retinal, in combination with opsin, to alter the photoreceptor sensitivities<ref>Article Opsin 1</ref>.

===Colour Vision===

Sandbox 173: Difference between revisions

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 5: / Line 5: @@
 ===G Protein-Coupled Receptors===
-Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signalling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref>Article 20</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref>Article 12</ref>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref>Article 20</ref>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case transducin, which interacts with the cytoplasmic loops of the receptor<ref>Article 10</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref>Article 20</ref>.
+Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signalling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref>Article 20</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref>Article 12</ref>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref>Article 20</ref>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case [http://en.wikipedia.org/wiki/Transducin transducin], which interacts with the cytoplasmic loops of the receptor<ref>Article 10</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref>Article 20</ref>.
@@ Line 26: / Line 26: @@
 ===Retinal Chromophore of Rhodospin===
-Rhodopsin consists of an opsin apoprotein and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in <font color='#FFFF00'>yellow</font>) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref>Article 19</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref>Article 12</ref>. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in <font color='#00FF00'>green</font>) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore <ref>Article 4</ref>. The protonated Schiff base of rhodopsin is stabilized through <scene name='Sandbox_173/Glu113/1'>Glutamine 113</scene> residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state<ref>Article 20</ref>.
+Rhodopsin consists of an opsin [http://en.wikipedia.org/wiki/Apoprotein apoprotein] and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in <font color='#FFFF00'>yellow</font>) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref>Article 19</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref>Article 12</ref>. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in <font color='#00FF00'>green</font>) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore <ref>Article 4</ref>. The protonated Schiff base of rhodopsin is stabilized through <scene name='Sandbox_173/Glu113/1'>Glutamine 113</scene> residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state<ref>Article 20</ref>.
 As this ligand is bound in the 12-s-''trans'' conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation<ref>Article 2</ref>. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation <ref>Original article</ref>.
@@ Line 55: / Line 55: @@
 <applet load='1u19' size='300' color='black' frame='true' align='right' caption='Phosphorylation of Rhodospin. The generated structure is from Chain A.'/>
 ====Signalling Cascade and Polarization of the Cell Membrane====
-The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref>Article 6</ref>.   Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates cGMP-specific phosphodiesterase by binding and removing its inhibitory subunit<ref>Textbook</ref>.
+The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref>Article 6</ref>.   Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates [http://en.wikipedia.org/wiki/CGMP-specific_phosphodiesterase_type_5 cGMP-specific phosphodiesterase] by binding and removing its inhibitory subunit<ref>Textbook</ref>.
 The cGMP phosphodiesterase is an integral protein of the retina with its active site on the cytoplasmic side of the disk. Its inhibitory subunit tightly binds to it in the dark and suppresses its activity.  The now activated phosphodiesterase degrades many molecules of cGMP, efficiently decreasing the concentration of cGMP <ref>Textbook</ref>. This results in the closing of the cGMP-gated cation channels in the plasma membrane of the outer segment. The cell hyperpolarizes due to the decrease in the influx of sodium and calcium ions, which results in the decrease of the release of glutamate into the synaptic cleft. This electric signal of this hyperpolarization is sent to the brain through ranks of interconnecting neurons and then through the optic nerve<ref>Article 6</ref>.
@@ Line 61: / Line 61: @@
 ====Recovery of the Pre-stimulus State====
 In the event of a decrease in light intensity, GTP is hydrolyzed and the α-subunit of transducin reassociates with the βγ subunits, releasing the inhibitory subunit of phosphodiesterase. This subunit reassociates with phosphodiesterase and inhibits its activity<ref>Textbook</ref>.
-The concentration of cGMP is returned to the “dark” state by the conversion of GTP to cGMP by guanylyl cyclase, activated through the efflux of calcium ions through the sodium/calcium ion exchanger. The reduction in the concentration of calcium ions also inhibits phosphodiesterase activity. Both actions reopen the cation channels and restore the system to pre-stimulus state<ref>Textbook</ref>.
+The concentration of cGMP is returned to the “dark” state by the conversion of GTP to cGMP by [http://en.wikipedia.org/wiki/Guanylate_cyclase guanylyl cyclase], activated through the efflux of calcium ions through the sodium/calcium ion exchanger. The reduction in the concentration of calcium ions also inhibits phosphodiesterase activity. Both actions reopen the cation channels and restore the system to pre-stimulus state<ref>Textbook</ref>.
 ====Phosphorylation and Deactivation of Rhodopsin====
-Rhodopsin kinase phosphorylates rhodopsin and arrestin binds to the phosphorylated domain of rhodopsin, preventing further signal transduction from Metarhodopsin II of activated rhodopsin and transducin<ref>Article 3</ref>. It phosphorylates both Metarhodopsin II and cone opsins. The majority of the phosphorylation sites are in the cytoplasmic C-terminal region of rhodopsin with seven hydroxy-amino acids. The most favoured amino acids are <scene name='Sandbox_173/Phosphorylated_sites/1'>Serine 338, Serine 343, Serine 334, Threonine 335 and Threonine 336</scene><ref>Article 7</ref>, and these residues form an arrangement in rhodopsin that does not appear to be exposed to the solvent. Interactions with the C-terminal tail and a portion of the Cytoplasmic loop 3 appear to be broken for the phosphorylation of the hydroxyl groups<ref>Article 9</ref>. For the next cycle of activation of rhodopsin, rhodopsin has to be dephosphorylated, and have the all-''trans'' retinal replaced with the 11-''cis'' retinal<ref>Article 19</ref>.
+[http://en.wikipedia.org/wiki/Rhodopsin_kinase Rhodopsin kinase] phosphorylates rhodopsin and [http://en.wikipedia.org/wiki/Arrestin arrestin] binds to the phosphorylated domain of rhodopsin, preventing further signal transduction from Metarhodopsin II of activated rhodopsin and transducin<ref>Article 3</ref>. It phosphorylates both Metarhodopsin II and cone opsins. The majority of the phosphorylation sites are in the cytoplasmic C-terminal region of rhodopsin with seven hydroxy-amino acids. The most favoured amino acids are <scene name='Sandbox_173/Phosphorylated_sites/1'>Serine 338, Serine 343, Serine 334, Threonine 335 and Threonine 336</scene><ref>Article 7</ref>, and these residues form an arrangement in rhodopsin that do not appear to be exposed to the solvent. Interactions with the C-terminal tail and a portion of the Cytoplasmic loop 3 appear to be broken for the phosphorylation of the hydroxyl groups<ref>Article 9</ref>. For the next cycle of activation of rhodopsin, rhodopsin has to be dephosphorylated, and have the all-''trans'' retinal replaced with the 11-''cis'' retinal<ref>Article 19</ref>.
 Altogether, the different states of rhodopsin which include the short-lived, photo-rhodopsin, batho-rhodopsin, and lumi-rhodopsin, and longer-lived meta-rhodopsins give information about the structural status of the molecule during activation<ref>Article 9</ref>.
@@ Line 75: / Line 75: @@
 ===Activity===
-Opsin is the [http://en.wikipedia.org/wiki/Apoprotein apoprotein] component of rhodopsin. Its ability to activate transducin is modulated by both 11-''cis'' retinal and the all-''trans'' retinal; the 11-''cis'' retinal reduces its activity while the all-''trans'' retinal enhances it through non-covalent interactions <ref>Article Opsin 1</ref>. This may give insight on the ability of all-''trans'' retinal, in combination with opsin, to alter the photoreceptor sensitivities<ref>Article Opsin 1</ref>.
+The ability of opsin to activate transducin is modulated by both 11-''cis'' retinal and the all-''trans'' retinal; the 11-''cis'' retinal reduces its activity while the all-''trans'' retinal enhances it through non-covalent interactions <ref>Article Opsin 1</ref>. This may give insight on the ability of all-''trans'' retinal, in combination with opsin, to alter the photoreceptor sensitivities<ref>Article Opsin 1</ref>.
 ===Colour Vision===