Journal Article

Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes

Maywood, Elizabeth S., Dupré, Sandrine M., Rajamohan, Francis, Bechtold, David A., Gibbs, Julie E., Takahashi, Joseph S., Walton, Kevin M., Lu, Wei-Qun, Knafels, John, Zawadzke, Laura E., Hastings, Michael H., Sneed, Blossom, Chesham, Johanna E., Wager, Travis T., Meng, Qing-Jun, Loudon, Andrew S. I., Li, Jian, Ohren, Jeffrey F.

2010

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Base Sequence / Biological Sciences / Bioluminescence / Casein Kinase 1 epsilon - antagonists & inhibitors / Casein Kinase 1 epsilon - physiology / Casein Kinase Idelta - antagonists & inhibitors / Casein Kinase Idelta - deficiency / Casein Kinase Idelta - genetics / Casein Kinase Idelta - physiology / Cell lines / chromosome mapping / Circadian rhythm / Circadian Rhythm - drug effects / Circadian Rhythm - physiology / Circadian rhythms / Enzymes / Fibroblasts / Gene expression / Gene Knockdown Techniques / Genetic mutation / In Vitro Techniques / Inhibitory concentration 50 / Kinases / locomotion / Locomotor activity / Mice / Mice, Knockout / Mice, Transgenic / Mutation / Neurons / Neurosciences / non-specific serine/threonine protein kinase / Period Circadian Proteins - metabolism / Pharmacology / post-translational modification / Protein isoforms / Protein Kinase Inhibitors - pharmacology / proteins / Pyrimidines - pharmacology / Receptors, Vasoactive Intestinal Peptide, Type II - deficiency / Receptors, Vasoactive Intestinal Peptide, Type II - genetics / RNA, Small Interfering - genetics / Rodents / Suprachiasmatic Nucleus - drug effects / Suprachiasmatic Nucleus - physiology / transcription (genetics) / Vehicles