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Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes
Qing-Jun Meng, Elizabeth S. Maywood, David A. Bechtold, Wei-Qun Lu, Jian Li, Julie E. Gibbs, Sandrine M. Dupré, Johanna E. Chesham, Francis Rajamohan, John Knafels, Blossom Sneed, Laura E. Zawadzke, Jeffrey F. Ohren, Kevin M. Walton, Travis T. Wager, Michael H. Hastings, Andrew S. I. Loudon and Joseph S. Takahashi
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 34 (August 24, 2010), pp. 15240-15245
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/27862224
Page Count: 6
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Circadian pacemaking requires the orderly synthesis, posttranslational modification, and degradation of clock proteins. In mammals, mutations in casein kinase 1 (CK1) ε or δ can alter the circadian period, but the particular functions of the WT isoforms within the pacemaker remain unclear. We selectively targeted WT CK1ε and CK1δ using pharmacological inhibitors (PF-4800567 and PF-670462, respectively) alongside genetic knockout and knockdown to reveal that CK1 activity is essential to molecular pacemaking. Moreover, CK1δ is the principal regulator of the clock period: pharmacological inhibition of CK1δ, but not CK1ε, significantly lengthened circadian rhythms in locomotor activity in vivo and molecular oscillations in the suprachiasmatic nucleus (SCN) and peripheral tissue slices in vitro. Period lengthening mediated by CK1δ inhibition was accompanied by nuclear retention of PER2 protein both in vitro and in vivo. Furthermore, phase mapping of the molecular clockwork in vitro showed that PF-670462 treatment lengthened the period in a phase-specific manner, selectively extending the duration of PER2-mediated transcriptional feedback. These findings suggested that CK1δ inhibition might be effective in increasing the amplitude and synchronization of disrupted circadian oscillators. This was tested using arrhythmic SCN slices derived from Vipr2 −/− mice, in which PF-670462 treatment transiently restored robust circadian rhythms of PER2::Luc bioluminescence. Moreover, in mice rendered behaviorally arrhythmic by the Vipr2 −/− mutation or by constant light, daily treatment with PF-670462 elicited robust 24-h activity cycles that persisted throughout treatment. Accordingly, selective pharmacological targeting of the endogenous circadian regulator CK1δ offers an avenue for therapeutic modulation of perturbed circadian behavior.
Proceedings of the National Academy of Sciences of the United States of America © 2010 National Academy of Sciences