## Visual cycle (the conversion of 11-cis-retinal to all-trans-retinal and all-trans-retinol)
<ul>
 <li>
 Light exposure initiates the visual cycle (sensory transduction of the visual system). It acts
 like a second messenger system in reverse
 </li>
 <li>
 In the resting state (dark): Na channels are held open by cGMP, keeping the photoreceptor outer
 segment in a state of depolarisation
 </li>
</ul>
<HotTopic>
 The only photoreaction in the visual cycle
</HotTopic>
<ul>
 <li>
 Photon energy is absorbed by 11-cis-retinal (the ligand of rhodopsin) which converts to the
 stable all-trans-retinal form
 </li>
 <li>
 All-trans-retinal activates rhodopsin which is converted to bathorhodopsin and then
 lumirhodopsin
 </li>
</ul>
<ul>
 <li>
 The isomerisation of 11-cis-retinal to all-trans-retinal is known as bleaching
 </li>
 <ul>
 <li>
 All-trans-retinal converts to all-trans retinol which does not fit within the rhodopsin
 transmembrane loops and thus rhodopsin is converted to opsin during bleaching.&nbsp;
 </li>
 <li>All-trans-retinol diffuses away to be absorbed by the RPE</li>
 </ul>
</ul>
<ul>
 <li>Lumirhodopsin becomes metarhodopsin I and then metarhodopsin II</li>
 <ul>
 <li>The conversion of metarhodopsin I to metarhodopsin II is the only reversible step</li>
 </ul>
 <li>Metarhodopsin II decays to metarhodopsin III by releasing all-trans-retinal</li>
</ul>

## Phototransduction
<ul>
 <li>Occurs within photoreceptor outer segments</li>
 <li>1 photon is needed to trigger the process</li>
 <li>Outer segments remain depolarised by open cGMP controlled Na channels</li>
 <ul>
 <li>Sodium and calcium enter the cell</li>
 </ul>
 <li>Light stimulation starts the visual cycle producing metarhodopsin (aka enzyme R*)</li>
 <ul>
 <li>
 A quantum of light breaks the 11-cis double bond of retinal and opsin undergoes conformational
 changes
 </li>
 <li>
 The metarhodopsin II molecule is the activated state and begins a cascade that controls cation
 flow into the outer segment
 </li>
 <li>
 One molecule of metarhodopsin II activates hundreds of molecules of transducin (thus
 amplifying the reaction)
 </li>
 </ul>
 <li>Transducin: a G-protein which dissociates into subunits</li>
 <ul>
 <li>Alpha subunit activates rod phosphodiesterase (rod PDE)</li>
 <li>Rod PDE hydrolyses cGMP to 5&rsquo;-GMP</li>
 <li>One molecule of PDE can hydrolyse 600 molecules of cGMP (further amplification)</li>
 </ul>
 <li>The target is the cGMP-gated cationic channel on the outer segment membrane.</li>
 <ul>
 <li>cGMP is hydrolysed and its concentration decreases&nbsp;</li>
 <ul>
 <li>Therefore Na channels close, preventing sodium entry</li>
 <li>This leads to hyperpolarisation (the cell develops negative charge)</li>
 </ul>
 </ul>
 <li>
 Hyperpolarisation leads to closure of voltage-regulated calcium gates and reduced calcium influx
 </li>
 <li>Hyperpolarization prevents glutamate release from the synaptic terminal</li>
</ul>

## Inhibition of photocascade
<ul>
 <li>Can occur at many stages</li>
 <ul>
 <li>When the light goes off, the rod returns to its dark state</li>
 <li>Rhodopsin can be inactivated by phosphorylation or binding to arrestin</li>
 <li>Activated PDE can recombine with its gamma subunits</li>
 <li>
 The transducin alpha subunit is inactivated by hydrolysis and rejoins its beta-gamma complex
 </li>
 <li>
 Reduced calcium influx during phototransduction in light conditions stimulates recoverin
 activity which activates guanylate cyclase
 </li>
 <ul>
 <li>Guanylate cyclase replenishes cGMP to reopen ion channels</li>
 </ul>
 </ul>
</ul>

## Cone phototransduction
<ul>
 <li>
 Cone phototransduction is comparatively insensitive compared to rod, but faster and can adapt to
 ambient illumination
 </li>
 <ul>
 <li>Greater light means faster and more accurate cone response</li>
 </ul>
 <li>Cones show neurally-mediated negative feedback</li>
 <ul>
 <li>Horizontal cells synapse antagonistically back to cones</li>
 <li>They release GABA: an inhibitory neurotransmitter&nbsp;</li>
 <li>This protects the cone from being overloaded</li>
 <li>
 Hence cones have a greater flicker fusion frequency by turning off rapidly so they can respond
 to new stimuli faster
 </li>
 </ul>
</ul>

## Vitamin A/retinol metabolism and recycling
<ul>
 <li>After releasing from opsin, all-trans-retinal is recycled differently by rods vs cones</li>
 <li>
 Cone chromophores are reisomerised within the retina to regenerate 11-cis-retinal which
 recombines with bleached rhodopsin
 </li>
 <li>
 Rod pigments are converted to all-trans-retinol within the retina by retinol dehydrogenase
 </li>
 <ul>
 <li>
 All-trans-retinol is then transported by interphotoreceptor retinoid binding protein (IRBP) to
 the RPE
 </li>
 </ul>
 <li>
 IRBP produced y photoreceptors accounts for 70% of soluble protein in the interphotoreceptor
 matrix (space between outer segments and RPE)
 </li>
 <li>
 In RPE, all-trans-retinol is isomerised (in the dark) to 11-cis-retinol, then bound to CRALBP to
 become 11-cis-retinal-CRALBP and transferred back to the photoreceptors on IRBP to reattach to
 rhodopsin
 </li>
 <li>
 IRBP&rsquo;s main function is the transport of retinoids between photoreceptors and the RPE and
 protects the plasma membranes from damaging from high retinoid concentrations
 </li>
 <ul>
 <li>Note: all-trans-retinol can also enter the RPE from the choriocapillaris</li>
 </ul>
</ul>
<ul>
 <li>Vitamin A:</li>
 <ul>
 <li>
 A provitamin in the yellow and red carotenoid pigments in vegetables (eg. carrots), liver,
 fish oils, dairy
 </li>
 <li>Fat-soluble (thereforereduced availability in malabsorption syndromes)</li>
 <ul>
 <li>Other fat-soluble vitamins are: D, E and K.</li>
 </ul>
 <li>Stored in the liver as retinyl ester and hydrolyzed to retinol</li>
 <ul>
 <li>Retinol is combined with serum retinol binding protein to deliver to RPE</li>
 </ul>
 <li>Essential for corneal and conjunctival health</li>
 <ul>
 <li>Required for epithelial keratin expression and glycoprotein synthesis</li>
 <li>Essential for the inhibition of proteolytic enzymes</li>
 </ul>
 </ul>
</ul>
<ClinicalCorrelate>
 
 Vitamin A deficiency leads to poor corneal wound healing, Bitot&rsquo;s spots and punctate
 epithelial erosions (even corneal necrosis: keratomalacia), nyctalopia, xerosis
 
</ClinicalCorrelate>
<ul>
 <li>
 Bitot&rsquo;s spot: corynebacterium xerosis release gas as a byproduct and produce foamy
 conjunctival lesions
 </li>
</ul>

Vision

Visual Cycle And Phototransuction

Intro

FRCOphth Part 1 Study Notes

Orbit and ocular adnexae

Orbit

Extraocular Muscles

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Corneal Physiology

AC to Lens

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Vitreous

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