A novel mechanism controlling resetting speed of the circadian clock to environmental stimuli.

ABSTRACT: Many aspects of mammalian physiology are driven through the coordinated action of internal circadian clocks. Clock speed (period) and phase (temporal alignment) are fundamental to an organism's ability to synchronize with its environment. In humans, lifestyles that disturb these clocks, such as shift work, increase the incidence of diseases such as cancer and diabetes. Casein kinases 1? and ? are closely related clock components implicated in period determination. However, CK1? is so dominant in this regard that it remains unclear what function CK1? normally serves. Here, we reveal that CK1? dictates how rapidly the clock is reset by environmental stimuli. Genetic disruption of CK1? in mice enhances phase resetting of behavioral rhythms to acute light pulses and shifts in light cycle. This impact of CK1? targeting is recapitulated in isolated brain suprachiasmatic nucleus and peripheral (lung) clocks during NMDA- or temperature-induced phase shift in association with altered PERIOD (PER) protein dynamics. Importantly, accelerated re-entrainment of the circadian system in vivo and in vitro can be achieved in wild-type animals through pharmacological inhibition of CK1?. These studies therefore reveal a role for CK1? in stabilizing the circadian clock against phase shift and highlight it as a novel target for minimizing physiological disturbance in shift workers.

SUBMITTER: Pilorz V 

PROVIDER: S-EPMC3988889 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other