Retinoids in Vision

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When photons of light enter the eye, the retina converts them into an electrical signal through a biochemical process called phototransduction. This signal is then relayed to the visual cortex of the brain, where visual perception occurs. The visual system allows us to continually perceive light throughout our lives because it has the ability to regenerate proteins and the light-sensitive chromophore. 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 the 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 to 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 the development of rational approaches to the treatment of human visual diseases. We propose to examine four fundamental steps in the visual cycle and how each step is involved in the quenching of phototransduction and the regeneration of rhodopsin. We would like to (1) investigate the role of photoreceptor dehydrogenases in phototransduction and the retinoid cycle, including the role of RDH12 and prRDH, and its substrate, all-trans-RAL, in dark adaptation; (2) purify and characterize the isomerization complex; (3) purify and characterize retinosomes, the ester storage particles of the visual cycle; characterize these structures in mice lacking ADRP, one of the pillar proteins of retinosomes; and (4) characterize LRAT enzymes on the structural, functional, and physiological level. Studies proposed in this application will add new biochemical and physiological information to steps in the retinoid cycle that are as yet poorly understood but which are critical for the normal function of photoreceptors.