The long-term goal of the study is to characterize the melatonin system of retina and related aspects of visual cell physiology with an emphasis on cellular and intercellular mechanisms of melatonin biosynthesis and receptor-mediated actions. In the retina, melatonin synthesis occurs in photoreceptor cells and is involved in the regulation of photoreceptors, pigment epithelial cells, and dopamine neurons. Together, dopamine and melatonin have a central role in the modulation of visual sensitivity and photoreceptor-pigment epithelium metabolism. Melatonin and dopamine have opposing actions related to photoperiod, with dopamine mediating effects of light and melatonin mediating effects of darkness. One major specific aim is to determine the biochemical mechanisms that regulate melatonin biosynthesis. To achieve this aim, experiments will be done to (1) investigate the signaling cascade that couples photoreceptor membrane potential to expression of enzymes in the melatonin biosynthetic pathway, and (2) determine how this cascade is influenced by the photoreceptor circadian clock. The second major specific aim is to clarify the cellular mechanisms involved in melatonin's actions in retina. To achieve this aim, experiments will investigate (1) the mechanisms for inhibition of dopamine release by melatonin, (2) the functional coupling of dopamine receptors and melatonin receptors, (3) the signal transduction mechanism employed by melatonin receptors on pigment epithelial cells, and (4) the mechanisms for regulation of melatonin receptor function. These studies will be done with integrated biochemical, pharmacological, electrophysiological, and cell and molecular biological methodologies. The investigators contend that achievement of their specific aims in this proposal will contribute significantly to the understanding of visual cell physiology and the pathological processes that underlie photoreceptor degeneration.
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