Molecular Mechanisms of Melatonin Action on the Rat Suprachiasmatic Nucleus: An in Vitro Analysis
"Daily rhythms in behavior, physiology, and metabolism are synchronized to the solar cycle by the suprachiasmatic nucleus (SCN) of the mammalian brain. Cells of the SCN undergo a near 24-hour pattern of cellular events that convey time-of-day information to target organs. The endogenous nature of this dock is based in a molecular feedback loop involving ""clock"" genes, kinases, and small molecules that cycle with a period that approximates one day. Additionally, the SCN generates a near 24-hour pattern of spontaneous neural activity that may communicate timing between cells of the SCN as well as in targets of SCN projections. The timing of the molecular and neural oscillations of the SCN can be adjusted by various stimuli, including the pineal hormone melatonin. SCN sensitivity to melatonin is temporally gated in that the SCN is responsive to melatonin at two times of day - dusk and dawn. At these times, melatonin advances the timing of peak spontaneous neuronal activity in a protein kinase C (PKC)-dependent pathway mediated through the melatonin type 2 (MT 2) receptor subtype. Since oscillations in dock genes underlie circadian rhythmicity, it follows that changes in the timekeeping mechanism likely require adjustments of dock gene expression patterns. This study sought to examine the molecular mechanisms by which melatonin induces changes in dock timing in the SCN. Here I show that the induction of the dock genes Per1 and Per2 is necessary for melatonin to elicit a phase advance in neural activity, an effect that is abolished by inhibiting PKC. Furthermore, the effects of melatonin on Per1 and Per2 are mediated by cis-acting regulatory enhancer sequences termed E-boxes in the promoters of these dock genes. Finally, transient rearrangement of the actin cytoskeleton plays a crucial role in conveying the melatonin signal from the plasma membrane into the cell to induce phase shifts. This evidence supports a link between melatonin signal transduction mechanisms requiring actin remodeling and Per1 and Per2 transcription in resetting the SCN circadian dock."
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign