OPSIN • all-ftwu-rf tinal
Figure 7. Flow of retinoids in the vertebrate eye. 1 l-cis-Retinal is coupled to opsin apoproteins in both rod and cone photoreceptor cells and is photoisomerized to all-/nmy-retinal by light. The regeneration of 1 l-c/.v-retinal, the universal chromophore of vertebrate retina, is a complex process involving photoreceptors and adjacent retinal pigment epithelial cells (RPE). For details see the text and an extensive review , condensation products with phosphatidylethanolamine . The cytoplasmic-assessable all-iraws-retinal is reduced in a NADPH-dependent reaction catalyzed by retinol dehydrogenases (Figure 7, reaction b), members of the short-chain alcohol dehydrogenase super-family [242,243]. This reaction is the rate-limiting step in the retinoid cycle after intense bleaching , All -trans-retinal also combines non-covalently with opsin (depicted by the blue arrow in Figure 7) in a different binding pocket from the original retinylidene-binding site [236,237]. As a consequence of elevated Gt stimulating activity, as compared to free opsin and lack of activity by rhodopsin, and the slow reduction process, opsin'all-ira/w-retinal complexes are possible candidates for the desensitizing form of the receptor during bleaching adaptation. This complex is also a substrate for RK, and when opsin is phosphorylated within this complex, it binds arrestin tightly . Next, retinol diffuses through two cell membranes to the RPE (Figure 7, indicated by yellow), where it is trapped as insoluble fatty acid esters in a reaction catalyzed by lecithin-retinol acyl transferase (LRAT)  (Figure 7, reaction c). Although the isomerization process is unknown on the chemical level, retinyl esters are, most likely, converted into more reactive intermediates and isomerized to 11-m-retinol (Figure 7, reaction d; see  for a more in-depth discussion of the potential mechanisms of isomerization).
Highly abundant RPE-specific protein RPE65 is believed to play a critical role in this process (see ). Finally, 1 l-cis-retinol is oxidized in a NADH/NADP-dependent reaction catalyzed by 11 -m-retinol dehydrogenases (Figure 7, reaction e), also like all-/ra7M-retinol-specifIc enzymes, members of the short-chain alcohol dehydrogenases . 11-c/s-retinal diffuses back to ROS, where it irreversibly combines with opsin to form the 11-m-retinylidene chromophore, and fully regenerated rhodopsin (Figure 7, reaction f). ll-cw-Retinal could alternatively be produced by direct photoisomerization of all-ira/iy-retinal with the help of retinal G-protein-coupled receptor (RGR) protein in RPE and Müller cells . Several mutations in genes involved in the retinoid cycle are associated with a subset of human retinopathies, including Stargard's fundus flavimaculatus, recessive retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), or fundus albipunctatus (FA) (reviewed in ).
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