Recovery and Supply of the Chromophore
Still under construction
Recent update from: 02.07.2006
This page introduces you to the proteins and pathways involved in the retinoid metabolism of the visual cascade.
If you click on a protein on the right, you will receive a description of the chosen step and further pages providing information on that protein can be accessed.
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Supply of retinoids to photoreceptors is one of the crucial points in retinal nutrition. Retinoids are supplied as vitamin A (retinol, Rol) which is taken up from food in the small intestine by
Cellular Retinol-binding Protein 2 (CRBP2)
and delivered by a
Serum Retinol-binding Protein (SRBP, RBP4)/transthyretin
via the choroidal vasculature to the target RPE cells.
SRBP-Rol binds to a cell surface receptor (p63) (
(3)) which supports unloading of Rol to
Cellular Retinol-binding Protein 1 (CRBP1)
CRBP1 is an intracellular transporter of atRol which carries the retinoid inside the cell. After esterification of atRol by Lecithin/Retinol Acyltransferase (LRAT) to form retinyl esters (Ry). The all-trans retinyl ester (atRy) is converted by Isomerohydrolase to 11cRy.
Ry is the major storage form of retinol in the RPE (99% of which 75% are stored in the 11cRy pool in RPE). For further steps in the biochemical pathways it is converted to 11cRol and an acyl rest by Retinol Ester Hydrolase (REH). ((14), (18)). This proteins is localised in RPE membranes.
11cRol, its aldehyde 11cRAl, and their all-trans isomers are different forms of retinoids cycling in the process of vision. 11cRol is oxidized by 11-cis Retinol Dehydrogenase (RDH) to 11cRAl in the RPE. 11-cis-RDH belongs to the family of short chain alcohol dehydrogenases. It is a integral membrane-bound stereospecific enzyme of the microsomal subfraction which uses NADH as electron source (19). 11-cis-RDH has been immunolocalised to the RPE (20).
11cRol and 11cRAl are carried by Cellular Retinaldehyde-binding Protein (CRAlBP) to and from RDH (5). CRAlBP is a watersoluble intracellular protein that interacts closely with11-cis-RDH (7). It shows positive immunoreactivity in RPE and Müller cells (9). Additionally CRAlBP acts as a substrate transporter for several other proteins in the retinoid metabolism like Retinyl Ester Synthetase (6) , or LRAT.
In photoreceptor outer segments retinoids are bound to photo pigment apoproteins where they are used as light perceiving ligands. Photons lead to isomerization of 11cRAl to atRAl which changes the inactive form of RHO to the active meta II form. (see also: Visual Cascade)
For recovery of the chromophor atRAl is released from meta II to all-trans-RDH which catalyses the reduction of atRAl to atRol at very slow reaction rates in ROS using NADPH as a cofactor (11). This is an indication that inside the retinol cycle more than one RDH are in use since 11-cis-RDH utilizes NADH as proton donor (19).
(11)In photoreceptors ABC-Cassette Transporter Retina (ABCR) is discussed to be involved in atRAl metabolism. According to Sun et al. ABCR might extract atRAl from ROS disks which is linked to PE to suppress biochemical noise in the visual cascade . Thus explaining A2-E (a derivate of atRAl and PE and a major component of lipofuscin) accumulation in RPE of Stargardt and AMD patients deficient of ABCR activity. A2-E accumulated in ROS disk would therefore be accumulated in RPE after digestion of ROS
atRol diffuses through the plasma membrane into the interphotoreceptor space where it is bound to Interphotoreceptor Retinoid-binding Protein (IRBP ) (16). IRBP , which is synthesised by the neural retina and secreted by photoreceptor cells, is the predominant protein of the IPM (8) (10). It predominantly binds atRAl and atRol (4), although IRBP can also bind other lipid ligands (13) . Due to its retinoid binding properties IRBP is the protein that shuttles the chromophore between the RPE and the photoreceptor outer segment, from and to regeneration (13).
Edwards et al. considered IRBP to contribute to an atRAl sink in IPM that constitutes a constant supply of chromophore to the photoreceptor and protection of retinoids from degradation.
A meanwhile solved role in retinoid metabolism plays , a RPE-specific protein of microsomal membranes (12) . Recent data indicate RPE65 to be the central protein in atRol isomeration when it was identified as the long sought isomerohydrolase(15). is assisted by RDH5 and CRALBP since free 11-cis retinol is water insoluble and instable when not bound to a transport protein.
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This site is maintained and edited by
Dr. rer. medic. Markus Preising, Dipl.Biol.
Molecular Genetics Laboratory
Department of Paediatric Ophthalmology, Strabismology and Ophthalmogenetics
University of Regensburg
Head: Prof. Dr. med. Birgit Lorenz