The goal is to understand the control of the chromophore of rhodopsin over the processes of visual excitation and bleaching adaptation. The hypothesis is that the rhodopsin has a distinctly different conformation from its product of bleaching, opsin, and these differences in conformation affect the interaction with other retinal proteins that in turn control the sensitivity of the photoreceptor. The change of the chromophore structure allows the manipulation of the physiology and the biochemistry of the photoreceptor. Derivatives of the chromophore, chosen to test some specific aspect of the interaction of the chromophore with the protein, will be synthesized. Physiological measurements in isolated rods and cones will be related to in vitro measurements of the biochemical processes that are involved. The native and analogue pigments will be studied by a variety of mass spectral and other spectroscopic techniques and related to the biochemical findings. Both the transduction process and the mechanisms of pigment regeneration and termination of bleaching adaptation by retinoids will be studied. The role of retinoid transport and the retinoid binding proteins will be examined by retinoid analogues. For certain conditions of clinical retinal degenerations, data from several laboratories reveal the presence of point mutations or polymorphisms in various retinal proteins, which would lead to abnormal interactions of these proteins in the visual transduction and adaptation processes. Derivatives of the chromophore of rhodopsin can induce abnormal conformations of rhodopsin that in turn affect the interaction with proteins in the transduction process. The experiments proposed here offer a means for studying these clinical disorders at the basic biochemical and physiological levels.
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