MOLECULAR DISSECTION OF 2 DISTINCT ACTIONS OF MELATONIN ON THE SUPRACHIASMATIC CIRCADIAN CLOCK

The pineal hormone melatonin elicits two effects on the suprachiasmati c nuclei (SCN): acute neuronal inhibition and phase-shifting. Melatoni n evokes its biological effects through G protein-coupled receptors. S ince the Mel(1a) melatonin receptor may transduce the major neurobiolo gical actions of melatonin in mammals, we examined whether it mediates both melatonin effects on SCN function by using mice with targeted di sruption of the Mel(1a) receptor. The Mel(1a) receptor accounts for al l detectable, high affinity melatonin binding in mouse brain. Function ally, this receptor is necessary for the acute inhibitory action of me latonin on the SCN. Melatonin-induced phase shifts, however, are only modestly altered in the receptor-deficient mice; pertussis toxin still blocks melatonin-induced phase shifts in Mel(1a) receptor-deficient m ice. The other melatonin receptor subtype, the Mel(1b) receptor, is ex pressed in mouse SCN, implicating it in the phase-shifting response. T he results provide a molecular basis for two distinct, mechanistically separable effects of melatonin on SCN physiology.