A Novel Mechanism Controlling Resetting Speed of the Circadian Clock to Environmental Stimuli

Summary

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 1δ and ε are closely related clock components implicated in period determination. However, CK1δ is so dominant in this regard that it remains unclear what function CK1ε normally serves. Here, we reveal that CK1ε dictates how rapidly the clock is reset by environmental stimuli. Genetic disruption of CK1ε in mice enhances phase resetting of behavioral rhythms to acute light pulses and shifts in light cycle. This impact of CK1ε 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 CK1ε. These studies therefore reveal a role for CK1ε in stabilizing the circadian clock against phase shift and highlight it as a novel target for minimizing physiological disturbance in shift workers.

Highlights

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  CK1ε ^−/− mice exhibit enhanced phase resetting to advancing and delaying stimuli

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  Selective pharmacological inhibition of CK1ε with PF4800567 enhances resetting

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  Accelerated resetting is observed in central and peripheral clocks

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  Accelerated resetting reduces physiological desynchrony

Abstract

Pilorz et al. reveal a new role for CK1ε in stabilizing the phase of the circadian clock. Using genetic and pharmacological targeting, they demonstrate that CK1ε dictates how rapidly the clock is reset by photic (light) and nonphotic (temperature) stimuli and thus highlight a novel target for reducing physiological disturbance in shift work.