Cheng Hai-Ying M, Obrietan Karl, Cain Sean W, Lee Bo Young, Agostino Patricia V, Joza Nicholas A, Harrington Mary E, Ralph Martin R, Penninger Josef M
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr Gasse 3-5, A-1030 Vienna.
Neuron. 2004 Sep 2;43(5):715-28. doi: 10.1016/j.neuron.2004.08.021.
Circadian rhythms of physiology and behavior are generated by biological clocks that are synchronized to the cyclic environment by photic or nonphotic cues. The interactions and integration of various entrainment pathways to the clock are poorly understood. Here, we show that the Ras-like G protein Dexras1 is a critical modulator of the responsiveness of the master clock to photic and nonphotic inputs. Genetic deletion of Dexras1 reduces photic entrainment by eliminating a pertussis-sensitive circadian response to NMDA. Mechanistically, Dexras1 couples NMDA and light input to Gi/o and ERK activation. In addition, the mutation greatly potentiates nonphotic responses to neuropeptide Y and unmasks a nonphotic response to arousal. Thus, Dexras1 modulates the responses of the master clock to photic and nonphotic stimuli in opposite directions. These results identify a signaling molecule that serves as a differential modulator of the gated photic and nonphotic input pathways to the circadian timekeeping system.
生理和行为的昼夜节律由生物钟产生，生物钟通过光或非光信号与周期性环境同步。目前人们对各种生物钟同步途径之间的相互作用和整合了解甚少。在这里，我们表明，类Ras G蛋白Dexras1是主生物钟对光和非光输入反应性的关键调节因子。Dexras1的基因缺失通过消除对NMDA的百日咳敏感昼夜反应来减少光同步。从机制上讲，Dexras1将NMDA和光输入与Gi/o和ERK激活耦合。此外，该突变极大地增强了对神经肽Y的非光反应，并揭示了对唤醒的非光反应。因此，Dexras1以相反的方向调节主生物钟对光和非光刺激的反应。这些结果确定了一种信号分子，它作为昼夜计时系统中门控光和非光输入途径的差异调节因子。
