Sandbox 173: Difference between revisions

The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasmic 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 name="Article6"/>. 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 name="Textbook">Nelson, D., and Cox, M. Lehninger Principles of Biochemistry. 2008. 5th edition. W. H. Freeman and Company, New York, New York, USA. pp. 462-465.</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 name="Textbook"/>. 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 name="Article6"/>.

===Visual Signal Termination===

====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 name="Textbook"/>.  

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 name="Textbook"/>.

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

[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 name="Article3"/>. 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 name="Article7">PMID:9667002</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 name="Article9"/>. 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 name="Article19"/>.