title: 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 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.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Violetta
authors.initials: V
authors.lastname: Pilorz
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Cunningham
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: West
authors.affiliation: Pfizer Global Research and Development, Groton, CT 06340, USA.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Andrew S I
authors.initials: AS
authors.lastname: Loudon
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. Electronic address: david.bechtold@manchester.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Bechtold
mesh_terms: D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D002940:Circadian Rhythm / Q000502:physiology; D008297:Male; D051379:Mice; D017440:Photoperiod; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000502:physiology
chemical_list: D048149:Casein Kinase 1 epsilon