Melatonin is a methoxyindole synthesized in 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 cellular function of photoreceptors, pigment epithelial cells, and dopamine neurons. Together with dopamine, melatonin appears to play a pivotal role in the modulation of visual sensitivity and adaptation by photoperiod and circadian clocks. A retinal circadian clock regulates two enzymes in the melatonin biosynthetic pathway: tryptophan hydroxylase (TPH) and serotonin N-acetyltransferase (AANAT). In addition, AANAT 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 must be elucidated. Specifically, experiments will be conducted to investigate: 1) the molecular basis for the effects of light and cAMP on AANAT protein stability and degradation; 2) the organization of retinal circadian clocks and the molecular mechanisms for coupling clock output to AANAT expression; 3) the signaling mechanism for entrainment of the photoreceptor circadian oscillator by light. 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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