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Science 320 (5878): 949-953

Copyright © 2008 by the American Association for the Advancement of Science

cAMP-Dependent Signaling as a Core Component of the Mammalian Circadian Pacemaker

John S. O'Neill,1* Elizabeth S. Maywood,1 Johanna E. Chesham,1 Joseph S. Takahashi,2 Michael H. Hastings1{dagger}

Abstract: The mammalian circadian clockwork is modeled as transcriptional and posttranslational feedback loops, whereby circadian genes are periodically suppressed by their protein products. We show that adenosine 3',5'-monophosphate (cAMP) signaling constitutes an additional, bona fide component of the oscillatory network. cAMP signaling is rhythmic and sustains the transcriptional loop of the suprachiasmatic nucleus, determining canonical pacemaker properties of amplitude, phase, and period. This role is general and is evident in peripheral mammalian tissues and cell lines, which reveals an unanticipated point of circadian regulation in mammals qualitatively different from the existing transcriptional feedback model. We propose that daily activation of cAMP signaling, driven by the transcriptional oscillator, in turn sustains progression of transcriptional rhythms. In this way, clock output constitutes an input to subsequent cycles.

1 Medical Research Council (MRC) Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
2 Howard Hughes Medical Institute, Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208–3520, USA.

* Present address: Center for Systems Biology at Edinburgh, University of Edinburgh, Edinburgh EH9 3JU, UK.

{dagger} To whom correspondence should be addressed. E-mail: mha{at}mrc-lmb.cam.ac.uk

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