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,wedo not fully understand the mechanisms that shape the properties ofMAPK/ERKsignaling in the SCN, andhow 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. ©2012 the authors.