Neuropharmacology of Circadian Rhythms

Zatz, M.

Abstract

Circadian rhythms and environmental lighting regulate a number of endocrine and behavioral functions. Arguably, the best understood hormonal rhythm is that of the pineal gland, which secretes the hormone melatonin almost entirely at night. Unlike cells from rat pineal, dispersed cells from chick pineal remain rhythmic, and responsive to light, in culture. This year, we showed that the melatonin rhythm is driven by an endogenous clock that changes gene expression. Melatonin is made from serotonin, which, in turn, is made from the amino acid tryptophan in two steps, the first of which is mediated by the enzyme tryptophan hydroxylase (TPH). Levels of mRNA for TPH display a circadian rhythm in cultured chick pineal cells, and an increased amplitude with temperature. The key enzyme in the synthesis of melatonin is serotonin N-acetyltransferase (SNAT). We found that the mRNA levels for SNAT display a circadian rhythm in cultured chick pineal cells, that much of the regulation of SNAT enzyme activity by light and forskolin occurs posttranscriptionally, and that its mRNA levels are increased by protein synthesis inhibitors. Future work in this direction will attempt to track back from specific gene regulation to clock mechanisms. Other work this year extended previous attempts to track forward from photoreception toward the clock: light was found to increase the turnover of inositides, which may participate in the regulation of intracellular calcium fluxes and, thereby, in entrainment of the circadian pacemaker.