Non-photic phase shifting of the circadian clock: role of the extracellular signal-responsive kinases I/II/mitogen-activated protein kinase pathway
Non-photic phase shifting of the circadian clock: role of the extracellular signal-responsive kinases I/II/mitogen-activated protein kinase pathway
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DOI：
10.1111/j.1460-9568.2008.06533.x
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发表时间：
2008-12-01
影响因子：
3.4
通讯作者：
Hagel, Kimberly
中科院分区：
文献类型：
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作者：
Antle, Michael C.;Tse, Floria;Hagel, Kimberly
主生物钟位于视交叉上核(SCN)，主要通过暴露在光中与外部世界同步。基于唤醒或活动的第二类刺激也可以以一种与光不同的方式重新设置仓鼠的生物钟。这些非光相移背后的机制尚不清楚，尽管已经涉及到规范时钟基因和即刻早期基因的抑制。最近，有丝分裂原激活的蛋白激酶(MAPK)之一，即细胞外信号反应激酶I/II(ERK)的抑制被认为与暗脉冲的相移有关，暗脉冲是一种既有光成分又有非光成分的刺激。我们研究了ERK/MAPK通路在午间开始的3h睡眠剥夺反应的相变中的作用。约四分之三的动物在此过程中表现出约3小时的大幅时相提前。移位的动物显示出SCN中磷酸化ERK(p-ERK)的显著减少。那些在睡眠剥夺期间灌流的动物在SCN腹外侧部的不同部分也显示出p-ERK的免疫反应。最后，向SCN注射U0126以阻止ERK的磷酸化显著降低p-ERK的水平，但不产生相移。这些数据表明，纯粹的非光操作能够改变SCN中MAPK通路的活性，下调SCN外壳的表达，激活SCN核心的一部分。
The master circadian clock, located in the suprachiasmatic nucleus (SCN), is synchronized to the external world primarily through exposure to light. A second class of stimuli based on arousal or activity can also reset the hamster circadian clock in a manner distinct from light. The mechanism underlying these non-photic phase shifts is unknown, although suppression of canonical clock genes and immediate early genes has been implicated. Recently, suppression of one of the mitogen-activated protein kinases (MAPK), namely extracellular signal-responsive kinases I/II (ERK), has been implicated in phase shifts to dark pulses, a stimulus with both photic and non-photic components. We investigated the involvement of the ERK/MAPK pathway in phase shifts in response to 3 h of sleep deprivation initiated at mid-day. About three-quarters of animals subjected to this procedure demonstrated large phase advances of about 3 h. Those that shifted exhibited a significant decrease in phosphorylated ERK (p-ERK) in the SCN. Those animals that were perfused during the sleep deprivation also exhibited immunoreactivity for p-ERK in a distinct portion of the ventrolateral SCN. Finally, injections of U0126 to the SCN to prevent phosphorylation of ERK significantly decreased levels of p-ERK but did not produce phase shifts. These data demonstrate that a purely non-photic manipulation is able to alter the activity of the MAPK pathway in the SCN, with downregulation in the SCN shell and activation in a portion of the SCN core.