Temporal regulation of light-induced extracellular signal-regulated kinase activation in the suprachiasmatic nucleus
Temporal regulation of light-induced extracellular signal-regulated kinase activation in the suprachiasmatic nucleus
复制标题
DOI：
10.1152/jn.00524.2003
复制
发表时间：
2003-12-01
影响因子：
2.5
通讯作者：
Obrietan, K
中科院分区：
文献类型：
--
作者：
Butcher, GQ;Lee, BY;Obrietan, K
通过p42/p44有丝分裂原活化蛋白激酶（MAPK）途径的信号转导已经被认为是将光耦合到位于视交叉上核（SCN）中的哺乳动物昼夜节律钟的中间事件。为了研究光输入如何动态调节MAPK通路的激活状态，我们使用不同的光刺激范例监测细胞外信号调节激酶（ERK）的激活。与对照组动物相比，没有暴露于光，15分钟的光暴露在夜间引发了ERK激活和ERK从胞质到细胞核的易位显着增加。ERK激活在光照后15 min达到峰值，然后在45 min内恢复到接近基础水平。MAPK通路可以被间隔45 min的光脉冲多次激活，表明MAPK级联反应迅速重置并将单个光脉冲分解为离散的信号事件。在恒定光照条件下（120分钟），ERK激活，核转位和失活的时间过程是类似的时间过程后观察到的15分钟的光处理。由15和120分钟的光暴露引起的ERK失活配置文件之间的平行关系表明，SCN细胞含有MAPK通路信号终止机制，限制了通路激活的持续时间。这一概念得到了以下观察结果的支持：小G蛋白Ras（MAPK途径的调节剂）在恒定光照条件下（持续120分钟）保持活性、GTP结合状态，表明光信息被传递到SCN，SCN细胞在光处理期间保持其反应性。SCN同时表达核MAPK磷酸酶（MKP-1和MKP-2）和胞浆MAPK磷酸酶Mkp-3，从而提供了终止光诱导ERK激活的机制。总的来说，这些观察结果提供了重要的新信息，关于MAPK级联反应的调节，一个信号中间体，耦合光重置SCN时钟。
Signaling via the p42/p44 mitogen activated protein kinase ( MAPK) pathway has been implicated as an intermediate event coupling light to entrainment of the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). To examine how photic input dynamically regulates the activation state of the MAPK pathway, we monitored extracellular signal-regulated kinase (ERK) activation using different light stimulus paradigms. Compared with control animals not exposed to light, a 15 min light exposure during the early night triggered a marked increase in ERK activation and the translocation of ERK from the cytosol to the nucleus. ERK activation peaked 15 min after light onset, then returned to near basal levels within similar to45 min. The MAPK pathway could be reactivated multiple times by light pulses spaced 45 min apart, indicating that the MAPK cascade rapidly resets and resolves individual light pulses into discrete signaling events. Under conditions of constant light (120 min), the time course for ERK activation, nuclear translocation, and inactivation was similar to the time course observed after a 15-min light treatment. The parallels between the ERK inactivation profiles elicited by a 15 and a 120 min light exposure suggest that SCN cells contain a MAPK pathway signal-termination mechanism that limits the duration of pathway activation. This concept was supported by the observation that the small G protein Ras, a regulator of the MAPK pathway, remained in the active, GTP-bound, state under conditions of constant light (120-min duration), indicating that photic information was relayed to the SCN and that SCN cells maintained their responsiveness for the duration of the light treatment. The SCN expressed both nuclear MAPK phosphatases (MKP-1 and MKP-2) and the cytosolic MAPK phosphatase Mkp-3, thus providing mechanisms by which light-induced ERK activation is terminated. Collectively, these observations provide important new information regarding the regulation of the MAPK cascade, a signaling intermediate that couples light to resetting of the SCN clock.