Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms

D. J. Kennaway, T. J. Varcoe, A. Voultsios, M. D. Salkeld, L. Rattanatray, M. J. Boden

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Circadian rhythms are generated through a transcription-translation feedback loop involving clock genes and the casein kinases CSNK1D and CSNK1E. In this study, we investigated the effects of the casein kinase inhibitor PF-670462 (50 mg/kg) on rhythmic expression of clock genes in the liver, pancreas and suprachiasmatic nucleus (SCN) as well as plasma corticosterone, melatonin and running behaviour in rats and compared them to the responses to a 4 h extension of the light phase. PF-670462 acutely phase delayed the rhythmic transcription of Bmal1, Per1, Per2 and Nr1d1 in both liver and pancreas by 4.5 ± 1.3 and 4.5 ± 1.2 h, respectively, 1 day after administration. In the SCN, the rhythm of Nr1d1 and Dbp mRNA expression was delayed by 4.2 and 4 h, respectively. Despite these changes, the time of peak plasma melatonin secretion was not delayed, although the plasma corticosterone rhythm and onset of wheel-running activity were delayed by 2.1 and 1.1 h, respectively. These changes are in contrast to the effects of the 4 h light extension, which resulted in delays in peak expression of the clock genes of less than 1 h and no change in the melatonin or corticosterone rhythms. The ability of the casein kinase inhibitor to bring about large phase shifts in the rhythms of major metabolic target tissues may lead to new drugs being developed to rapidly phase adjust circadian rhythms to alleviate the metabolic impact of shift work.

Original languageEnglish
Pages (from-to)195-206
Number of pages12
JournalMolecular and Cellular Biochemistry
Volume398
Issue number1-2
DOIs
Publication statusPublished or Issued - Jan 2015
Externally publishedYes

Keywords

  • Circadian
  • Corticosterone
  • Melatonin
  • Suprachiasmatic nucleus
  • Transcription factors

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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