cAMP-regulated dynamics of the mammalian circadian clock.
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.
Wang
Junwei
J
School of Informatics, Guangdong University of Foreign Studies, Guangzhou, China. wangjunweilj@yahoo.com.cn
Zhou
Tianshou
T
D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D001683:Biological Clocks; D002940:Circadian Rhythm / Q000502:physiology*; D003198:Computer Simulation; D003463:Cues; D000242:Cyclic AMP / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D056950:Period Circadian Proteins / Q000235:genetics; D017440:Photoperiod; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D000242:Cyclic AMP