The long-term objective of the proposed studies is to understand the regeneration of 11-cis-retinal, the universal chromophore of the vertebrate retina. 11-cis-Retinal is coupled to the protein opsin in both rod and cone photoreceptor cells and is photoisomerized to all-trans-retinal by light. The importance of inactivation and regeneration of photoactivated rhodopsin has become apparent recently, as malfunctions in the processing of this chromophore and the inhibition of rhodopsin regeneration lead to impairment of vision and the degeneration of photoreceptors. Elucidation of the molecular steps involved in the retinoid cycle would greatly contribute to our understanding of the basis of these disease states and provide a foundation for rational approaches to treatments. We propose to examine four fundamental steps of the visual cycle and how each step is involved in the quenching of phototransduction and the regeneration of rhodopsin. We would like to understand (1) the release of the photoisomerized chromophore from the binding pocket of opsin (the first step of the visual cycle), the role of all-trans-retinol dehydrogenase, and the role of all-trans-retinal during dark adaptation; (2) the chemistry and enzymology of the isomerization process that occurs in retinal pigment epithelial cells (RPE); (3) the contribution of reverse photoisomerization in the production of 11-cis-retinal in mouse RPE; and (4) the oxidation of 11-cis-retinol by RDH5 dehydrogenase (the final step of the visual cycle), the detoxification of RPE from non-functional 13-cis-retinoids, and the role of additional, novel dehydrogenase(s) involved in the cycle.
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