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 [241], condensation products with phosphatidylethanolamine [241]. 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 [244], 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 [239]. 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) [245] (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 [241] 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 [241]). 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 [242]. 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 [246]. 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 [241]).

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