title: Harmine lengthens circadian period of the mammalian molecular clock in the suprachiasmatic nucleus.
abstract: 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.
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST).
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kondoh
authors.forename: Saori
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Tatsunosuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Koyomi
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Nanako
authors.initials: N
authors.lastname: Itoh
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yasumoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Oike
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Doi
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Oishi
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D057906:Circadian Clocks / Q000187:drug effects*; D002940:Circadian Rhythm / Q000187:drug effects*; D004622:Embryo, Mammalian; D005347:Fibroblasts; D006247:Harmine / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D009474:Neurons; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D006247:Harmine; D008156:Luciferases