Circadian Clock-Controlled Regulation of cGMP-Protein Kinase G in the Nocturnal Domain

Abstract

The suprachiasmatic nucleus (SCN) circadian clock exhibits a recurrent series of dynamic cellular states, characterized by the ability of exogenous signals to activate defined kinases that alter clock time. To explore potential relationships between kinase activation by exogenous signals and endogenous control mechanisms, we examined clock-controlled protein kinase G (PKG) regulation in the mammalian SCN. Signaling via the cGMP-PKG pathway is required for light-or glutamate (GLU)-induced phase advance in late night. Spontaneous cGMP-PKG activation occurred at the end of subjective night in free-running SCN in vitro. Phasing of the SCN rhythm in vitro was delayed by ϳ3 hr after treatment with guanylyl cyclase (GC) inhibitors, PKG inhibition, or antisense oligodeoxynucleotide (␣ODN) specific for PKG, but not PKA inhibitor or mismatched ODN. This sensitivity to GC-PKG inhibition was limited to the same 2 hr time window demarcated by clock-controlled activation of cGMP-PKG. Inhibition of the cGMP-PKG pathway at this time caused delays in the phasing of four endogenous rhythms: wheel-running activity, neuronal activity, cGMP, and Per1. Timing of the cGMP-PKGnecessary window in both rat and mouse depended on clock phase, established by the antecedent light/dark cycle rather than solar time. Because behavioral, neurophysiological, biochemical, and molecular rhythms showed the same temporal sensitivities and qualitative responses, we predict that clock-regulated GC-cGMP-PKG activation may provide a necessary cue as to clock state at the end of the nocturnal domain. Because sensitivity to phase advance by light-GLU-activated GC-cGMP-PKG occurs in juxtaposition, these signals may induce a premature shift to this PKG-necessary clock state.

Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules

“…The NO-cGMP-PKG pathway is involved in circadian phase advances in response to light (28)(29)(30)(31)(32). A better knowledge of the transduction pathway might provide pharmacological tools for the treatment of circadian disorders, such as phase delay or advance of the human sleep-wake cycle, jet-lag, and shift work-related disturbances.…”

“…However, downstream of NO these pathways bifurcate, leading to different events that occur only during the early or the late night. During the late night, the activation of the guanylyl cyclase-cGMP-cGMP-dependent protein kinase (PKG) pathway is known to be involved in phase advances but not phase delays (28)(29)(30)(31)(32). Therefore, the accessibility of specific signaling pathways is fundamental for regulation of circadian timing.…”

Resetting Mechanism of Central and Peripheral Circadian Clocks in Mammals

“…In the mutant mice, only the light-induced phase delay is inhibited moderately, suggesting that PKGII is required for the photic induction of Per2 that delays the phase of the clock. Pharmacological studies, however, have implicated cGMP-PKG pathway as being critical for the phase advance by light in late night (Gillette and Mitchell, 2002;Tischkau et al, 2003b). This discrepancy should be resolved in future studies.…”

A neuropeptide speeds circadian entrainment by reducing intercellular synchrony

“…In the absence of VIP or its receptor, VPAC2R, SCN neurons fail to synchronize to each other and consequently many daily rhythms of the organism are lost (8)(9)(10)(11)(12). The addition of VIP to SCN cultures induces the production of Period (Per) 1 and 2 (13), two genes implicated in light-induced resetting (14)(15)(16), and shifts rhythms in behavior and SCN physiology (17)(18)(19)(20)(21). Notably, daily addition of VIP or an agonist to the VIP receptor, VPAC2R, entrains rhythms in SCN explants and Vip −/− SCN neurons (21,22).…”