title: Regulation of MAPK/ERK signaling and photic entrainment of the suprachiasmatic nucleus circadian clock by Raf kinase inhibitor protein.
abstract: Activation of the MAPK/ERK signaling cascade in the suprachiasmatic nucleus (SCN) is a key event that couples light to circadian clock entrainment. However, we do not fully understand the mechanisms that shape the properties of MAPK/ERK signaling in the SCN, and how these mechanisms may influence overt circadian rhythms. Here we show that Raf kinase inhibitor protein (RKIP) controls the kinetics of light-induced MAPK/ERK activity in the SCN and photic entrainment of behavioral rhythms. Light triggers robust phosphorylation of RKIP in the murine SCN and dissociation of RKIP and c-Raf. Overexpression of a nonphosphorylatable form of RKIP in the SCN of transgenic mice blocks light-induced ERK1/2 activation in the SCN and severely dampens light-induced phase delays in behavioral rhythms. Conversely, in RKIP knock-out (RKIP(-/-)) mice, light-induced ERK1/2 activity in the SCN is prolonged in the early and late subjective night, resulting in augmentation of the phase-delaying and -advancing effects of light. Reentrainment to an advancing light cycle was also accelerated in RKIP(-/-) mice. In relation to the molecular clockwork, genetic deletion of RKIP potentiated light-evoked PER1 and PER2 protein expression in the SCN in the early night. Additionally, RKIP(-/-) mice displayed enhanced transcriptional activation of mPeriod1 and the immediate early gene c-Fos in the SCN in response to a phase-delaying light pulse. Collectively, our data reveal an important role of RKIP in the regulation of MAPK/ERK signaling in the SCN and photic entrainment of the SCN clock.
authors.affiliation: Department of Biology, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6, Canada.
authors.forename: Ghadi
authors.initials: G
authors.lastname: Antoun
authors.forename: Pascale
authors.initials: P
authors.lastname: Bouchard-Cannon
authors.forename: Pascale Bouchard
authors.initials: PB
authors.lastname: Cannon
authors.forename: Hai-Ying Mary
authors.initials: HY
authors.lastname: Cheng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D057906:Circadian Clocks / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D049488:Phosphatidylethanolamine Binding Protein / Q000502:physiology*; D010775:Photic Stimulation / Q000379:methods*; D013493:Suprachiasmatic Nucleus / Q000201:enzymology / Q000502:physiology*
chemical_list: D049488:Phosphatidylethanolamine Binding Protein; C539308:Raf kinase inhibitory protein, mouse