CAMP-regulated dynamics of the mammalian circadian clock

Abstract

Previous molecular description of the mammalian timekeeping mechanism was based mainly on transcriptional/translational feedback loops (TTFLs). However, a recent experimental report challenges such a molecular architecture, showing that the cAMP signaling is an indispensable component of the mammalian circadian clock. In this paper, we develop a reduced mathematical model that characterizes the mammalian circadian network. The model with 8-state differential equations incorporates both TTFLs and cAMP-mediated feedback loop. In agreement with experimental observations, our results show that: (1) the model simulates sustained circadian (23.4-h periodic) oscillations in constant darkness and entrained circadian dynamics by light–dark cycles; (2) circadian rhythmicity is lost without cAMP signaling; (3) the system is resilient to large fluctuations in transcriptional rates; (4) it successfully simulates the phenotypes of Per1 −/−/ Per2 −/− double-mutant mice and Bmal1 −/− mutant mice. Our study implies that to understand the circadian pacemaking in suprachiasmatic nucleus neurons, the TTFLs should not be isolated from intracellular cAMP-dependent signaling.