Signaling in the suprachiasmatic nucleus: selectively responsive and integrative

The suprachiasmatic nucleus (SCN) contains a biological clock that generates timing signals that drive daily rhythms in behaviors and homeostatic functions. In addition to this pacemaker function, the SCN gates its own sensitivity to incoming signals, which permits appropriate temporal adjustment to achieve synchrony with environmental and organismic states. A series of time-domains, in which the SCN restricts its own sensitivity to a limited set of stimuli that adjust clock phase, can be distinguished. Pituitary adenylyl cyclase-activating peptide (PACAP) and cAMP directly reset clock phase during the daytime domain, both cause phase advances only during the clock's day-time domain, but are without effect at night. In contrast, acetylcholine and cGMP analogs phase advance the clock only when applied during the night. Sensitivity to light and glutamate arises concomitant with sensitivity to acetylcholine and cGMP. Light and glutamate cause phase delays in the early night, by elevating intracellular Ca2+ via neuronal ryanodine receptors. In late night, light and glutamate utilize a cGMP-mediated mechanism to induce phase advances. Nocturnal responses of SCN primed by light or glutamate can be modulated by effectors of phase-resetting in daytime, namely, PACAP and cAMP. Finally, the dusk and dawn domains are characterized by sensitivity to the pineal hormone, melatonin, acting through protein kinase C. These changing patterns of sensitivities demonstrate that the circadian clock controls multiple intracellular gates, which ensures that they can be opened selectively only at specific points in the circadian cycle. Discerning the molecular bases of these changes is fundamental to understanding integrative and regulatory mechanisms in the circadian system.