Ginty D D, Kornhauser J M, Thompson M A, Bading H, Mayo K E, Takahashi J S, Greenberg M E
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.
Science. 1993 Apr 9;260(5105):238-41. doi: 10.1126/science.8097062.
Mammalian circadian rhythms are regulated by a pacemaker within the suprachiasmatic nuclei (SCN) of the hypothalamus. The molecular mechanisms controlling the synchronization of the circadian pacemaker are unknown; however, immediate early gene (IEG) expression in the SCN is tightly correlated with entrainment of SCN-regulated rhythms. Antibodies were isolated that recognize the activated, phosphorylated form of the transcription factor cyclic adenosine monophosphate response element binding protein (CREB). Within minutes after exposure of hamsters to light, CREB in the SCN became phosphorylated on the transcriptional regulatory site, Ser133. CREB phosphorylation was dependent on circadian time: CREB became phosphorylated only at times during the circadian cycle when light induced IEG expression and caused phase shifts of circadian rhythms. These results implicate CREB in neuronal signaling in the hypothalamus and suggest that circadian clock gating of light-regulated molecular responses in the SCN occurs upstream of phosphorylation of CREB.
哺乳动物的昼夜节律由下丘脑视交叉上核（SCN）内的一个起搏器调节。控制昼夜起搏器同步的分子机制尚不清楚；然而，SCN中即刻早期基因（IEG）的表达与SCN调节的节律的同步紧密相关。分离出了能识别转录因子环磷酸腺苷反应元件结合蛋白（CREB）的活化、磷酸化形式的抗体。在仓鼠暴露于光线下几分钟内，SCN中的CREB在转录调控位点Ser133处发生磷酸化。CREB磷酸化依赖于昼夜节律时间：CREB仅在昼夜周期中光诱导IEG表达并导致昼夜节律相位偏移的时间才发生磷酸化。这些结果表明CREB在下丘脑的神经元信号传导中起作用，并提示SCN中光调节分子反应的昼夜节律门控发生在CREB磷酸化的上游。
