Editors' ChoiceCircadian Rhythms

A More Responsive Clock

Sci. Signal.  08 Apr 2014:
Vol. 7, Issue 320, pp. ec91
DOI: 10.1126/scisignal.2005343

Circadian clocks control various aspects of animal physiology. Oscillations in the transcription and translation of clock components occur over a 24-hour cycle and are coordinated with the day-night cycle. Changes in the day-night cycle induce changes in the molecular oscillations, enabling the clock to gradually get back in phase with the environment. In mammals, the central circadian clock operates in the suprachiasmatic nucleus (SCN) in the hypothalamus, and peripheral clocks in other organs are coordinated with this master clock. Pilorz et al. report that, whereas casein kinase 1δ (CK1δ) controls the periodicity of the clock, CK1ε determines how rapidly the clock can be reset in response to environmental changes. As assessed by behavioral, metabolic, and molecular criteria, CK1ε–/– mice reestablished central and peripheral clock coordination with the environment after changes in the light-dark cycle sooner than wild-type (WT) mice. When mice were kept in constant darkness for more than 2 weeks, a brief light pulse triggered a greater shift in the phase of the clocks of CK1ε–/– mice compared with the clocks of WT mice. Cultured SCN slices from CK1ε–/– mice exhibited greater phase shifting of circadian oscillations in response to application of the glutamate receptor agonist N-methyl-D-aspartate (NMDA), which mimics the input from light-detecting retinal neurons. Temperature also influences the circadian period, and SCN and lung tissues from CK1ε–/– mice were more responsive to changes in physiologically relevant temperature cycling than those from WT mice. Finally, treating mice with a drug that selectively inhibits CK1ε enhanced phase shifts in response to changes in the light-dark cycle. These greater phase shifts in mice lacking CK1ε function enabled the clock to reset more rapidly in response to environmental changes. CK1-mediated phosphorylation promotes degradation of the clock component PER2, leading the authors to propose that CK1ε activity reduces PER2 accumulation triggered by clock-resetting stimuli, thus reducing the magnitude of phase shifts to buffer the clock from transient or subtle changes in environmental stimuli. These findings also imply that pharmacological inhibition of CK1ε may sensitize the clock to resetting by environmental cues, which could be good news for shift workers and long-distance air travelers.

V. Pilorz, P. S. Cunningham, A. Jackson, A. C. West, T. T. Wager, A. S. I. Loudon, D. A. Bechtold, A novel mechanism controlling resetting speed of the circadian clock to environmental stimuli. Curr. Biol. 24, 766–773 (2014). [PubMed]

Correction: The original text incorrectly stated that the suprachiasmatic nucleus (SCN) is in the hippocampus and the compound N-methyl--aspartate (NMDA) is a neurotransmitter. This has been corrected.