Our long term goal is to understand the molecular, biochemical, signaling and functional properties of melatonin receptor subtypes in the mammalian central nervous system and to determine the role of this hormone in regulating the transmission of visual and circadian information. The overall goal of the present application is to elucidate the cellular and functional mechanism(s) through which activation of G-protein linked melatonin receptor subtypes (mt1 and MT2) and putative nuclear melatonin receptors (ROR-beta) within the circadian timing system (retina, SCN and IGL) affects circadian rhythms, regulates the entrainment of circadian rhythms following alterations in the light/dark cycle and modulates light responses reaching the circadian timing system. The experiments proposed in this application make use of new advances in the field of melatonin receptor research that occurred since the last submission. This includes the cloning of new mammalian melatonin receptor subtypes (mt1(Mel1a), MT2(Mel1b)], the discovery of specific and selective MT2 melatonin receptor antagonists as well as the establishment of mice lines with disruption of the mt1 melatonin receptor gene or the putative nuclear melatonin receptor gene, ROR-beta. The use of these probes and animal models permits to investigate the localization of melatonin receptor subtypes within the mammalian timing system, to establish their functional role in the regulation of circadian responses and interaction with light and to assess the consequence of their activation on signaling and gene regulation. We will address the following specific aims: 1) to determine within the circadian timing system the cellular localization of melatonin receptor subtypes (mt1 and MT2) and colocalization with the nuclear receptor ROR-beta, glutamate receptors (NMDA, AMPA, metabotropic), and per genes (per1, per2, per3); 2) to determine the melatonin receptor type involved in melatonin-mediated phase shifts of circadian rhythms and the signal transduction pathways altering clock activity in vitro; 3) to assess the receptor subtypes and mechanism(s) of light-melatonin interaction leading to advances in the phase of the clock; 4) to assess the mechanism(s) by which melatonin affects the rate of reentrainment following an abrupt phase advance of the dark cycle. The results of these studies will allow the rational design and synthesis of subtypes selective melatonin receptor agonists and antagonists that when administered at specific times will lead to either advances or delays of the clock. These novel therapeutic agents could be used for the treatment of insomnia or circadian disturbances involving abnormal phase advance (Advanced Sleep Phase Syndrome, endogenous depression, east jet flight) or phase delays (Delayed Sleep Phase Syndrome; seasonal affective disorders, west jet flight).
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