对光的感知除形成图像外，也影响睡眠节律和认知等多种生理过程，这些非成像视觉功能是由自感光视网膜神经节细胞（ipRGC）所介导的。ipRGC被光激活后，经GPCR-PLCb4通路产生光电流。其光响应具特殊的动力学特征，与ipRGC所介导的生理功能密切相关。我们预测在7TMR信号转导中极为重要的beta-arrestins可能参与ipRGC的光感受动力学，并繁育了在ipRGC内条件性敲除Arrb1/2的小鼠。双敲小鼠ipRGC在给予重复刺激时恢复响应所需的暗适应时间大幅度延长，表明Arrbs对ipRGC响应持续性光输入有重要意义，但作用路径和靶点有待阐明。本申请将使用电生理、药理学、和分子及行为水平的验证相结合的研究手段，解析Arrbs在ipRGC光信号转导中的作用位点和分子机制。实验结果将帮助我们理解ipRGC编码光信号的分子过程，并可能揭示beta-arrestins在信号转导中的新功能。

Perception of light is important not only for image-forming, but also many biological processes including photoentrainment of circadian rhythm, sleep regulation, cognition and mood. These functions are thus termed “non-image forming vision”, and they are largely mediated by a group of retinal ganglion cells, the intrinsically photosensitive retinal ganglion cells (ipRGCs). Phototransduction of ipRGCs is distinct from that of the traditional photoreceptor rods and cones, using G-protein coupled receptor and PLC pathways to activate TRPC6/7 and generate positive photocurrent. Their photo response also exhibit a slower onset and a slower decay compared to rods and cones. Such characteristics bestow ipRGCs the unique ability to integrate light over a prolonged period of time, which is of great physiological relevance considering many functions ipRGC carry out. We are hence interested in the details involved in the transduction and dynamics of ipRGC photo-responses, in particular, roles of beta-arrestins in this process. In preliminary attempt we observed that ipRGCs lacking Arrb1/2 (from conditional knock-out mice) showed normal response to single photo stimulation, but required significantly longer dark adaption before they could respond again, indicating deficits in recovery from prior response. We therefore propose to investigate in further detail the cellular mechanisms involved in the beta-arrestin associated recovery. We plan to use electrophysiology approaches aided by various pharmacological tools, in combination with molecular and behavioral examinations, to reveal the site of action of beta-arrestin in the photo-transduction/recovery of ipRGCs, and the molecular basis for their interactions. We expect to broaden our knowledge of the cellular processes underlying light-detection by ipRGC and provide insights for a better understanding of the physiological signals coded by light via ipRGCs.