cAMP-dependent signaling as a core component of the mammalian circadian pacemaker.
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.
O'Neill
John S
JS
Medical Research Council (MRC) Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Maywood
Elizabeth S
ES
Chesham
Johanna E
JE
Takahashi
Joseph S
JS
Hastings
Michael H
MH
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D020218:Response Elements; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D000067956:Adenylyl Cyclase Inhibitors; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; C017759:9-(tetrahydro-2-furyl)-adenine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000225:Adenine