Antagonistic effects of melatonin and PACAP on CREB phosphorylation in the rat suprachiasmatic nucleus

Circadian rhythms, generated by the major endogenous pacemaker, the suprachiasmatic nucleus (SCN) are synchronized with environmental light/dark cycles by photic information primarily transmitted via the retinohypothalamic tract (RHT). One putative neurotransmitter of the RHT is the pituitary adenylate cyclase-activating polypeptide (PACAP). The pineal hormone melatonin, whose synthesis and release is under the control of the pacemaker feeds back to the SCN, acting as a neuroendocrine signal of darkness. Like PACAP, melatonin is capable to affect the biological clock by phase-shifting of circadian rhythms. In the SCN the transcription factor cAMP response element binding protein (CREB) seems to be an important mediator between photic (and non-photic) inputs and protein synthesis. Here we demonstrate that in the rat SCN (1) CREB phosphorylation is induced during late subjective day by increasing intracellular concentrations of the second messengers cAMP or Ca2+ (2) PACAP can induce CREB phosphorylation during this time, and (3) melatonin inhibits the PACAP-induced phosphorylation. Our data show the possibility of CREB involvement in processing of light (or darkness) information even during subjective day. The potency of PACAP to affect gene expression in the SCN via activation of a transcription factor may give insight into rhythm entrainment, whereas the antagonistic effect of melatonin may mirror a feed-back loop within the circadian system.