title: The essential role of cAMP/Ca2+ signalling in mammalian circadian timekeeping.
abstract: Approximately daily, or circadian, rhythms are ubiquitous across eukaryotes. They are manifest in the temporal co-ordination of metabolism, physiology and behaviour, thereby allowing organisms to anticipate and synchronize with daily environmental cycles. Although cellular rhythms are self-sustained and cell-intrinsic, in mammals, the master regulator of timekeeping is localized within the hypothalamic SCN (suprachiasmatic nucleus). Molecular models for mammalian circadian rhythms have focused largely on transcriptional-translational feedback loops, but recent data have revealed essential contributions by intracellular signalling mechanisms. cAMP and Ca2+ signalling are not only regulated by the cellular clock, but also contribute directly to the timekeeping mechanism, in that appropriate manipulations determine the canonical pacemaker properties of amplitude, phase and period. It is proposed that daily auto-amplification of second messenger activity, through paracrine neuropeptidergic coupling, is necessary and sufficient to account for the increased amplitude, accuracy and robustness of SCN timekeeping.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. jso22@medschl.cam.ac.uk
authors.forename: John S
authors.initials: JS
authors.lastname: O'Neill
authors.forename: Akhilesh B
authors.initials: AB
authors.lastname: Reddy
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D057906:Circadian Clocks; D002940:Circadian Rhythm; D000242:Cyclic AMP / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D051379:Mice; D019899:Paracrine Communication; D020239:Receptor Cross-Talk; D015290:Second Messenger Systems; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000502:physiology
chemical_list: D000242:Cyclic AMP; D056926:CLOCK Proteins