Harmine Lengthens Circadian Period of the Mammalian Molecular Clock in the Suprachiasmatic Nucleus

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  • Kondoh Daisuke
    Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)
  • Yamamoto Saori
    Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)
  • Tomita Tatsunosuke
    Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)
  • Miyazaki Koyomi
    Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)
  • Itoh Nanako
    Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)
  • Yasumoto Yuki
    Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science
  • Oike Hideaki
    Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) National Food Research Institute, National Agriculture and Food Research Organization
  • Doi Ryosuke
    Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University
  • Oishi Katsutaka
    Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo

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The circadian clock is a cell-autonomous endogenous system that generates circadian rhythms in the behavior and physiology of most organisms. We previously reported that the harmala alkaloid, harmine, lengthens the circadian period of Bmal1 transcription in NIH 3T3 fibroblasts. Clock protein dynamics were examined using real-time reporter assays of PER2::LUC to determine the effects of harmine on the central clock in the suprachiasmatic nucleus (SCN). Harmine significantly lengthened the period of PER2::LUC expression in embryonic fibroblasts, in neuronal cells differentiated from neuronal progenitor cells and in SCN slices obtained from PER2::LUC mice. Although harmine did not induce the transient mRNA expression of clock genes such as Per1, Per2 and Bmal1 in embryonic fibroblasts, it significantly extended the half-life of PER2::LUC protein in neuronal cells and SCN slices. Harmine might lengthen the circadian period of the molecular clock by increasing PER2 protein stability in the SCN.

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