Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism
Light stimulates MSK1 activation in the suprachiasmatic nucleus via a PACAP-ERK/MAP kinase-dependent mechanism
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DOI：
10.1523/jneurosci.4361-04.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Obrietan, K
中科院分区：
文献类型：
--
作者：
Butcher, GQ;Lee, B;Obrietan, K
通过p42/44有丝分裂原激活蛋白激酶（MAPK）通路的信号传导已被证明是一个关键的细胞内信号传导事件，将光耦合到位于视交叉上核（SCN）的哺乳动物生物钟。由于MAPK通路的许多生理作用是由细胞外信号调节激酶（ERK）调节的激酶介导的，因此确定ERK在SCN中的激酶靶点是很有意义的。在这项研究中，我们研究了丝裂原和应激激活蛋白激酶1（MSK1）是否是SCN中ERK的下游靶点，以及它是否与时钟基因表达偶联。在这里，我们发现主观夜间的光刺激刺激MSK1丝氨酸360磷酸化，这是强健的激酶激活所必需的事件。光刺激后，活化的ERK和MSK1在SCN细胞核内共定位。MAP激酶激酶1/2抑制剂U0126[1,4-二氨基-2,3-二氨基-1,4-二（邻氨基苯基巯基）丁二烯]在体内可减弱MSK1的磷酸化。MSK1的磷酸化对深夜的光刺激比清晨的光刺激更敏感，这表明MSK1可能对光诱导的生物钟的相位提前和相位延迟有不同的贡献。垂体腺苷酸环化酶激活多肽（PACAP）（时钟夹带的调节因子）和MSK1磷酸化之间的潜在联系进行了研究。PACAP输注刺激MSK1磷酸化，而PACAP受体拮抗剂输注减弱SCN中光诱导的MSK1磷酸化。在报告基因分析中，MSK1通过cAMP反应元件结合蛋白依赖机制与mPeriod1偶联。总之，这些数据表明MSK1既是SCN内MAPK级联的下游靶点，也是时钟基因表达的调节因子。
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.