Molecular Mechanism of Photic Entrainment of Mammalian Circadian Clock

生物钟的产生和携带是哺乳动物应对环境变化和维持体内状态平衡的必然结果。在哺乳动物中，生物钟位于下丘脑视交叉上核（SCN），主要通过光刺激与环境的24小时节律同步。本实验室的一系列研究表明，此外，SCN在自主神经系统的调节中具有不可避免的作用。SCN有来自视网膜的直接神经元输入，导致生物钟与环境光/暗周期同步。在本研究项目中，我们研究了SCN中蛋白磷酸化在光/暗循环中的变化，发现BIT/SHPS-1在环境的亮度下发生酪氨酸磷酸化。BIT/SHPS-1是神经元细胞表面的一种跨膜糖蛋白，参与各种细胞外刺激的信号转导。抗bit单克隆抗体刺激其酪氨酸磷酸化诱导运动活动的昼夜相移和增强交感神经活动。冷暴露或2-脱氧葡萄糖注射也使酪氨酸磷酸化。这些结果表明BIT/SHPS-1参与了SCN对自主神经系统的光诱导和调控。

Generation and entrainment of circadian clock is innevitable for mammals to cope with environmental changes and maintain the homeostasis of internal body conditions. In mammals, the circadian clock is located at the suprachiasmatic nucleus of the hypothalamus (SCN), which is synchronized to the environmental 24h rhythms mainly by light stimulation. A series of studies in this laboratory have suggested that, in addition, the SCN has inevitable roles in regulation of the autonomic nervous systems. The SCN has direct neuronal inputs from the retina that leads to synchronization of the circadian clock to the environmental light/dark cycles. In this research projects, we have examined the changes in protein phosphorylation in the SCN during the light/dark cycles and found that BIT/SHPS-1 underwent tyrosine phosphorylation in response to the lightness of the environment. BIT/SHPS-1 is a transmembrane glycoprotein on the neuronal cell surfaces implicated in signal transduction of various extracellular stimuli.Anti-BIT monoclonal antibody that stimulates its tyrosine phosphorylation induced circadian phase shifts of locomotor activity and enhanced sympathetic nerve activities. It was also tyrosine-phosphorylated on cold-exposure or 2-deoxyglucose injection. These results indicate that BIT/SHPS-1 is involved in the photic entrainment and the regulation of the autonomic nervous system by the SCN.