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

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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.

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Abbreviations

Actb :

Beta actin

Bmal1 :

Brain and muscle ARNT-like protein 1, Arntl and Mop3

Nr1d1 :

Nuclear receptor subfamily 1, group D, member 1, also known as Rev erb alpha

Per1 :

Period 1

Per2 :

Period 2

Cry1 :

Cryptochrome 1

Cry2 :

Cryptochrome 2

Dbp :

D site of albumin promoter (albumin D-box) binding protein

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Acknowledgments

This work was supported by a grant (GNT1029869) from the National Health and Medical Research Council (NHMRC) of Australia to DJK. DJK is an NHMRC Senior Research Fellow. We thank Dr Jeffrey Sprouse and Lundbeck Research USA for the generous gift of PF-670462.

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The authors have no conflicts of interest.

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Authors and Affiliations

  1. Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5005, Australia

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

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  1. D. J. Kennaway
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  2. T. J. Varcoe
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  3. A. Voultsios
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  4. M. D. Salkeld
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  5. L. Rattanatray
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  6. M. J. Boden
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Correspondence to D. J. Kennaway.

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Kennaway, D.J., Varcoe, T.J., Voultsios, A. et al. Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms. Mol Cell Biochem 398, 195–206 (2015). https://doi.org/10.1007/s11010-014-2219-8

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  • DOI: https://doi.org/10.1007/s11010-014-2219-8

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