Abstract
SummaryMany 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
Accelerated Phase Resetting to Light in Mice Lacking CK1ε Casein kinase 1 (CK1)-mediated phosphorylation and degradation of PERIOD (PER) protein are crucial determinants of the pace of the circadian clock, and we and others have shown that CK1d is the principal isoform in regulating clock speed [1,2,3,4]
To determine whether increased phase resetting to light in CK1ε2/2 mice reflected an altered response within the suprachiasmatic nucleus (SCN) itself, we examined clock resetting in SCN slice cultures in response to the neurotransmitter analog N-methyl-D aspartate (NMDA)
Application of NMDA timed for the rise or decline of PER2 expression induced phase delays or advances, respectively, in the clockwork of both genotypes (Figures 2E and 2F), SCN tissue derived from CK1ε2/2 mice exhibited significantly greater phase delays (p < 0.05, two-way ANOVA; n = 5/group) and advances (p < 0.05, two-way ANOVA; n = 3–5/group). These findings demonstrate that loss of CK1ε activity significantly enhances light-induced phase shift of the SCN clockwork and indicate that the enzyme normally buffers the clock against perturbation across multiple phases of the cycle
Summary
Many aspects of mammalian physiology are driven through the coordinated action of internal circadian clocks. 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. 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 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
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