title: Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism.
abstract: Signaling via the p42/44 mitogen-activated protein kinase (MAPK) pathway has been shown to be a key intracellular signaling event that couples light to entrainment of the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). Because many of the physiological effects of the MAPK pathway are mediated by extracellular signal-regulated kinase (ERK)-regulated kinases, it was of interest to identify kinase targets of ERK in the SCN. In this study, we examined whether mitogen- and stress-activated protein kinase 1 (MSK1) is a downstream target of ERK in the SCN and whether it couples to clock gene expression. Here we show that photic stimulation during the subjective night stimulates MSK1 phosphorylation at serine 360, an event required for robust kinase activation. Activated ERK and MSK1 were colocalized in SCN cell nuclei after photic stimulation. The in vivo administration of the MAP kinase kinase 1/2 inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto) butadiene] attenuated MSK1 phosphorylation. MSK1 phosphorylation was more responsive to late-night than early-night photic stimulation, indicating that MSK1 may differentially contribute to light-induced phase advancing and phase delaying of the clock. The potential connection between pituitary adenylate cyclase-activating polypeptide (PACAP) (a regulator of clock entrainment) and MSK1 phosphorylation was examined. PACAP infusion stimulated MSK1 phosphorylation, whereas PACAP receptor antagonist infusion attenuated light-induced MSK1 phosphorylation in the SCN. In reporter gene assays, MSK1 was shown to couple to mPeriod1 via a cAMP response element-binding protein-dependent mechanism. Together, these data identify MSK1 as both a downstream target of the MAPK cascade within the SCN and a regulator of clock gene expression.
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Greg Q
authors.initials: GQ
authors.lastname: Butcher
authors.forename: Boyoung
authors.initials: B
authors.lastname: Lee
authors.forename: Hai-Ying M
authors.initials: HY
authors.lastname: Cheng
authors.forename: Karl
authors.initials: K
authors.lastname: Obrietan
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002940:Circadian Rhythm; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D003624:Darkness; D004789:Enzyme Activation; D017930:Genes, Reporter; D006801:Humans; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis; D056950:Period Circadian Proteins; D010766:Phosphorylation; D010775:Photic Stimulation; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000037:antagonists & inhibitors; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D012694:Serine / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000378:metabolism / Q000528:radiation effects*
chemical_list: C495402:Adcyap1 protein, mouse; D002070:Butadienes; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D009570:Nitriles; D009687:Nuclear Proteins; C539022:PER1 protein, human; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; C113580:U 0126; D012694:Serine; D019893:Ribosomal Protein S6 Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases