A new mammalian circadian oscillator model including the cAMP module

Abstract

In this paper, we develop a new mathematical model for the mammalian circadian clock, which incorporates both transcriptional/translational feedback loops (TTFLs) and a cAMP-mediated feedback loop. The model shows that TTFLs and cAMP signalling cooperatively drive the circadian rhythms. It reproduces typical experimental observations with qualitative similarities, e.g. circadian oscillations in constant darkness and entrainment to light–dark cycles. In addition, it can explain the phenotypes of cAMP-mutant and Rev-erbα−/−-mutant mice, and help us make an experimentally-testable prediction: oscillations may be rescued when arrhythmic mice with constitutively low concentrations of cAMP are crossed with Rev-erbα−/− mutant mice. The model enhances our understanding of the mammalian circadian clockwork from the viewpoint of the entire cell.