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rod visual cycle

Sunday 20 April 2008

The term “visual cycle” was coined by George Wald in the mid-1900’s to describe the ability of the eye to “re-cycle” vitamin A (vitamin A is a collective term for physiologically active retinoids) for the synthesis of visual pigments.

Over 50 years later, vision research scientists have now gathered a great deal of information on the rod (rhodopsin) visual cycle.

As originally proposed by Wald in 1968, the rod visual cycle requires the involvement of both the retina and the retinal pigment epithelium (RPE) in order to properly process the retinal chromophore released from bleached rod pigment (or rhodopsin).

Upon bleaching, all-trans retinal separates from opsin in the rod outer segment and is reduced to all-trans retinol by an NADPH-dependent all-trans specific retinol dehydrogenase.

It has been proposed that the rate of retinol production is limited by the availability of NADPH, which is dependent on ATP localized to the rod outer segment but derived from mitochondria in the rod inner segment.

All-trans retinol is then transferred from the retina to the RPE where it is esterified by the enzyme, lecithin:retinol acyltransferase (LRAT).

RPE65, another enzyme in the RPE, catalyzes the hydrolysis of the all-trans retinyl ester and uses the energy released in the hydrolytic reaction to isomerize all-trans retinol to 11-cis retinol.

Oxidation of 11-cis retinol to 11-cis retinal in humans is carried out by RDH5, an 11-cis specific retinol dehydrogenase and a member of the short chain acyl-CoA dehydrogenase (SCAD) family of proteins. Mutations in gene RDH5 result in Fundus albipunctatus phenotype. However, the knock out of RDH5 in mice, as well as the double knock out of RDH5 and RDH11 did not produce the expected phenotype, suggesting that the oxidation of 11-cis retinol to 11-cis retinal may involve an additional yet unidentified retinol dehydrogenases.

11-cis retinal then exits the RPE and transfers back to the retina to re-combine with opsin to form rhodopsin.

11-cis retinol can also be esterified by LRAT to form 11-cis retinyl ester which is stored in the RPE and later released by 11-cis retinyl ester hydrolase to supply chromophore for pigment synthesis.

It is also important to point out retinal G-protein coupled receptor (RGR) has also been identified to play key roles in the rod visual cycle. RGR is expressed in the RPE and in the Müller cells.

It is proposed that RGR forms a complex with retinol dehydrogenase 5 (RDH5) to isomerize all-trans retinal to 11-cis retinal under light illumination, thus providing an alternate pathway to obtain cis retinoids in the visual cycle.

However, recent data using single and double RGR/RDH knockout mouse models suggest that RGR’s role in the generation of cis retinoid for rod pigment regeneration may be not essential.

RGR has also been found to accelerate the conversion of retinyl esters to 11-cis retinal in a light independent manner. Accordingly, it has been proposed that RGR enhances isomerohydrolase activity in the dark.

Vitamin A

Vitamin A are fat soluble molecules which need facilitating factors (such as retinol binding proteins) to transfer in aqueous cytosolic and extracellular locations.

It is now well established that CRBP (cellular retinol binding protein, Type I) binds all-trans retinol, and CRALBP (cellular retinal binding protein) binds 11-cis retinal.

In the retina, both of these binding proteins are expressed in Müller cells; with all-trans retinol bound to CRBP while 11-cis retinol and 11-cis retinal are bound to CRALBP.

Vitamin A in the extracellular interphotoreceptor matrix is also associated with a retinoid binding protein known as interphotoreceptor retinoid binding protein (IRBP).

Although the transport function of these binding proteins is essential, it is not entirely clear whether some binding proteins truly associate with vitamin A for this purpose, since genetic deletion of IRBP show little loss of visual recovery in mice.

Another important function of retinoid binding proteins (such as CRBP and CRALBP) is their ability to remove vitamin A from the site of a reaction thereby shifting the equilibrium of the reaction (by mass action) and dictating the direction of the reaction in a pathway of the visual cycle.

See also

- cone visual cycle


- Muniz A, Villazana-Espinoza ET, Hatch AL, Trevino SG, Allen DM, Tsin AT. A novel cone visual cycle in the cone-dominated retina. Exp Eye Res. 2007 Aug;85(2):175-84. PMID: 17618621. Free in PMC