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

• DOI: 10.1523/jneurosci.23-20-07543.2003
• Publication Date: 2018-04-12T23:25:04Z
• Authors: Shelley A. Tischkau; E. Todd Weber; Sabra M. Abbott; Jennifer W. Mitchell; Martha U. Gillette
• Keywords: Neurons; 0303 health sciences; Indoles; Behavior, Animal; Carbazoles; Nuclear Proteins; Cell Cycle Proteins; Period Circadian Proteins; Darkness; Circadian Rhythm; Oligodeoxyribonucleotides, Antisense; Rats; Running; Kinetics; 03 medical and health sciences; Alkaloids; Cyclic GMP-Dependent Protein Kinases; Animals; Suprachiasmatic Nucleus; Enzyme Inhibitors; Cyclic GMP; Cells, Cultured

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 SCNin vitro. Phasing of the SCN rhythmin vitrowas delayed by ∼3 hr after treatment with guanylyl cyclase (GC) inhibitors, PKG inhibition, or antisense oligodeoxynucleotide (αODN) 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, andPer1. Timing of the cGMP-PKG-necessary 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.