Signaling in the suprachiasmatic nucleus: selectively responsive and integrative

Abstract

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 Ca(2+) 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.

Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules

“…Because there is no description of CNGCs or extracellular release of cGMP in the SCN, it is unlikely that these mechanisms underlie the effect of cGMP on photic entrainment. We and others have determined a clear role of PKG in light-induced phase shifts, suggesting that this is a likely mechanism to explain cGMP-mediated sildenafil effects (20,31).…”

“…The cAMP/PKA pathway has traditionally been involved in nonphotic resetting in the daytime domain (20,21). Application of cAMP analogs in vitro induces prominent phase advances in the subjective day but not in the subjective night (22).…”

In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus

“…Activation of MT 1 acutely inhibits the neuronal firing rate (Liu et al 1997;Gillette and Mitchell 2002;Jin et al 2003), while activation of the MT 2 phase shifts circadian rhythms of activity in vivo via activation of PKC (Dubocovich et al 1998;McArthur et al 1997;Hunt et al 2001).…”

Differential effects of constant light on circadian clock resetting by photic and nonphotic stimuli in Syrian hamsters

“…The effiects of GLU on the clock are gated in part via a circadian rhythm in expression of two classes of GLU receptors: NMDA and non-NMDA receptors (Gillette & Mitchell, 2002;Schurov eta/., 1999). Following light exposure during phases that shift the clock (subjective night), GLU release in the vlSCN initially activates the non-NMDA receptors, amino-methyl proprionic acid (AMPA) and Kainate (KA), depolarizing the cell and eventually removing Mg2' blockage of NMDA receptors.…”

“…Conversely, in the late subjective night NO triggers a pathway involving guanylyl cyclase (GC), cyclic GMP (cGMP), and protein b a s e G, leading to phase advances (Gillette & Mitchell, 2002). Another effect of increased intracellular calcium involves calmodulin (CaM) activation, thereby initiating CaM-dependent kinases and the phosphorylation of cyclic AMP (CAMP) response element-binding protein (CREB) (Schurov et al, 1999 induction by light at night (Kornhauser etal., 1990;Rusak etal., 1990 (Shigeyoshi etal., 1997).…”