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Volume 17, Number 2, Issue of January 15, 1997 pp. 659-666
Copyright ©1997 Society for Neuroscience

Coupling of Muscarinic Cholinergic Receptors and cGMP in Nocturnal Regulation of the Suprachiasmatic Circadian Clock

Received June 24, 1996; revised Oct. 17, 1996; accepted Nov. 12, 1996.

Chen Liu¹, Jian M. Ding^{1, 2}, Lia E. Faiman², and Martha U. Gillette^{1, 2, 3}

¹ Neuroscience Program and Departments of ² Cell and Structural Biology and ³ Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Acetylcholine has long been implicated in nocturnal phase adjustment of circadian rhythms, yet the subject remains controversial. Although the suprachiasmatic nucleus (SCN), site of the circadian clock, contains no intrinsic cholinergic somata, it receives choline acetyltransferase-immunopositive projections from basal forebrain and mesopontine tegmental nuclei that contribute to sleep and wakefulness. We have demonstrated that the SCN of inbred rats in a hypothalamic brain slice is sensitive to cholinergic phase adjustment via muscarinic receptors (mAChRs) only at night. We used this paradigm to probe the muscarinic signal transduction mechanism and the site(s) gating nocturnal responsiveness. The cholinergic agonist carbachol altered the circadian rhythm of SCN neuronal activity in a pattern closely resembling that for analogs of cGMP; nocturnal gating of clock sensitivity to each is preserved in vitro. Specific inhibitors of guanylyl cyclase (GC) and cGMP-dependent protein kinase (PKG), key elements in the cGMP signal transduction cascade, blocked phase shifts induced by carbachol. Further, carbachol administration to the SCN at night increased cGMP production and PKG activity. The carbachol-induced increase in cGMP was blocked both by atropine, an mAChR antagonist, and by LY83583, a GC inhibitor. We conclude that (1) mAChR regulation of the SCN is mediated via GCcGMPPKG, (2) nocturnal gating of this pathway is controlled by the circadian clock, and (3) a gating site is positioned downstream from cGMP. This study is among the first to identify a functional context for mAChR-cGMP coupling in the CNS.

Key words: suprachiasmatic nucleus; acetylcholine; carbachol; circadian rhythm; guanylyl cyclase; muscarinic receptor; cyclic GMP; cGMP-dependent protein kinase; KT5823; LY83583; enzyme activity assay; scintillation proximity assay; sleep

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