cAMP-dependent signaling as a core component of the mammalian circadian pacemaker

John S. O'Neill, Elizabeth S. Maywood, Johanna E. Chesham, Joseph S. Takahashi, Michael H. Hastings

Research output: Contribution to journalArticlepeer-review

337 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)949-953
Number of pages5
Issue number5878
StatePublished - May 16 2008

ASJC Scopus subject areas

  • General


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