Melatonin Limits Transcriptional Impact of PhosphoCREB in the Mouse SCN Via the Mel1a Receptor

In the mouse, activity phase-shifts of the endogenous clock in the suprachiasmatic nucleus (SCN) are associated with phosphorylation of the transcription factor Ca2+/cAMP responsive element binding protein (CREB). CREB phosphorylation is induced by the retino-hypothalamic transmitter pituitary adenylate cyclase-activating polypeptide (PACAP). As detected by immunohistochemistry in SCN slices from wild-type mice, melatonin completely blocked PACAP-stimulated CREB phosphorylation at low concentrations (1 nM). In Mel1a melatonin receptor-deficient mice, the PACAP-induced CREB phosphorylation was inhibited only at melatonin concentrations of 100 nM. This inhibition was, however, blunted by blocking the Mel1b melatonin receptor. Thus, melatonin modulates PACAP-mediated retinal stimuli for clock entrainment primarily via the Mel1a melatonin receptor through molecular interaction within the cAMP-signalling pathway.