Melatonin is a methoxyindole synthesized in the retina and pineal gland under the influence of circadian clocks. In retina, melatonin synthesis occurs in photoreceptor cells. Retinal melatonin is involved in the regulation of the cellular function of photoreceptors, retinal pigment epithelial (RPE) cells, and dopamine neurons. Together with dopamine, melatonin appears to play a pivotal role in the modulation by photoperiod and circadian clocks of visual sensitivity and metabolism in the photoreceptor-pigment epithelial complex. A retinal circadian clock regulates two enzymes in the melatonin biosynthetic pathway: tryptophan hydroxylase (TPH) and serotonin N-acetyltransferase (NAT). In addition, NAT is regulated by light and a signaling cascade that links photoreceptor membrane potential to cAMP-dependent phosphorylation. The long-term goal of the study is to characterize the melatonin system of retina and related aspects of visual cell physiology. To this end, cellular and molecular mechanisms in the regulation of melatonin biosynthesis will be explored. Specifically, experiments will be conducted to investigate: (1) the signal transduction cascade that regulates the effects of light and darkness on NAT activity in photoreceptor cells; (2) the molecular basis for the effects of light and cAMP on NAT mRNA and protein levels; (3) the molecular mechanisms for coupling the circadian clock to NAT and TPH gene expression; and (4) the localization of NAT in the retina and brain. These studies will be conducted using an integrated research approach involving biochemical, pharmacological, and cell and molecular biological methodologies. The research is significant because it characterizes cellular and biochemical systems that play an important role in the regulation of retinal physiology and photoreceptor cell function. It is anticipated that characterization of these systems will contribute to the understanding of visual cell physiology and some of the pathological processes that underlie photoreceptor degeneration.
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