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Second messenger systems
Second messengers such as cyclic AMP (cAMP) and cyclic GMP (cGMP) relay signals from cell surface receptors to target molecules inside the cell. cGMP is synthesized from GTP by guanylyl cyclases and exerts its actions through cGMP-gated cation channels, cGMP-dependent protein kinases, and cGMP-regulated phosphodiesterases. It is a key regulator in phototransduction in the eye, where it acts directly on cGMP-gated cation channels in rod cells to keep them open in response to light. Mutations impacting cGMP levels can cause retinal diseases like Leber congenital amaurosis and retinitis pigmentosa.
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Second messenger systems
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- 2. Second messengers aremolecules that relay signals received at receptors on the cell surface — such as the arrival of protein hormones, growth factors, etc. — to target molecules in the cytosol and/or nucleus. Cyclic AMP, Cyclic GMP, Inositol Triphosphate, Diacylglycerol, Calcium ions, Nitric Oxide.
- 3. Earl W. Sutherland,Jr. The Nobel Prize in Physiology or Medicine 1971 was awarded to Earl W. Sutherland, Jr. "for his discoveries concerning the mechanisms of the action of hormones".
- 4. • cGMP issynthesised from GTP by two isoforms of guanylyl cyclase, one which functions when nitric oxide (soluble GC) is present and the other which acts as a receptor for natriuretic peptides (membrane bound GC). • cGMP exerts its actions through cGMP-gated cation channels, cGMP-dependent protein kinases (PKGs), and cGMP-regulated phosphodiesterases (PDEs). • cGMP is a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. It also relaxes smooth muscle tissues. In blood vessels, relaxation of vascular smooth muscles lead to vasodilation and increased blood flow. cGMP is also a secondary messenger in phototransduction in the eye. cGMP
- 5. cGMP mediated Photo-transduction inRod cells Direct support for the role of cGMP in rod-cell activity has been obtained in patch- clamping studies using isolated patches of rod outer-segment plasma membrane, which contains abundant cGMP-gated cation channels. When cGMP is added to the cytosolic surface of these patches, there is a rapid increase in the number of open ion channels. cGMP acts directly on the ion channels to keep them open. Three or four cGMP molecules must bind per channel in order to open it; this allosteric interaction makes channel opening very sensitive to small changes in cGMP levels.
- 6. Human eye contains2 types of photoreceptors: Rods and Cones. Rods contain a G- protein coupled receptor called Rhodopsin, made of opsin and 11-cis retinal
- 7. Rhodopsin is activatedas a result of the absorption of light by the associated small molecule 11-cis- retinal, which then isomerizes to all-trans-retinal, inducing a conformational change in the rhodopsin protein.
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- 9. Retinal diseases dueto mutations in RetGC1 and PDE6 • Leber Congenital Amaurosis (LCA) A form of congenital or early-infantile blindness due to mutations in retinal GC leading to lack of cGMP. • Cone- red dystrophy 6 (CORD6) Cone rod dystrophy is evidenced by deterioration of photoreceptor cone and rod cells and is caused due to the elevated levels of cGMP due to mutations in GC. • Retinitis pigmentosa Retinitis pigmentosa (RP) is a group of genetic disorders that affect the retina’s ability to respond to light. This inherited disease causes a slow loss of vision, beginning with decreased night vision and loss of peripheral (side) vision. It is due to mutations in cGMP phosphodiesterase enzymes in the retinal cells.
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