至今仍有约100种孤儿G蛋白偶联受体，因内源性配体的未知，限制了该类重要潜在药物靶点的功能研究。为打破这一瓶颈，根据孤儿G蛋白偶联受体和光敏蛋白Channelrhodopsin-2（ChR2）在进化上保守的跨膜结构特征，我们首次提出构建ChR2-孤儿GPCR嵌合体（opto-XR，孤儿GPCR的胞外和跨膜段替换为ChR2的相应序列），实现光控激活孤儿受体。以Gi型GPR37为例，首次构建opto-GPR37，证实光控激活opto-GPR37可诱导GPR37信号转导及行为反应。在本课题中，（1）利用opto-GPR37在精确时间和特定细胞激活GPR37，研究GPR37对焦虑、抑郁和社交行为的作用，探索其新功能；(2)在构建opto-GPR6（Gs型）的基础上,探讨该方法在其他孤儿受体功能性研究的广泛适用性。本项目将有助于建立孤儿受体功能研究的新策略, 为GPCR药物新靶点开发提供依据。

There are still ~100 orphan GPCRs that lack the endogenous ligands, which hamper functional dissection of this class of important drug targets. To overcome this major limit and based on the evolutionarily conserved transmembrane , we propose that the opto-orphan GPCR chimera (opto-XR, by replacing the extracellular and transmembrane fragments of Channelrhodopsin-2 with the corresponding parts of orphan GPCRs). The opto-XR can bypass the endogenous ligand and directly activate orphan GPCR by light. To illustrate this approach, we have successfully designed the opto-GPR37 construct (GPR37 belongs to the Gi type) and demonstrated that its activation by the light elicited signal transduction and behavioral changes. In this project, we will build upon this finding to fully develop the novel opto-orphan GRPR approach for functional dissection of orphan GPCR from two aspects: 1) By leveraging the unique ability of opto-GPR37 to activate GPR37 signaling in time- and cell-specific manner, we will determine the role of GPR37 in modulation of anxiety-, depression- and social interaction-related behaviors. 2) We will further explore the general applicability of opto-orphan GPCR strategy for other orphan GPCRs by evaluating our newly designed opto-GPR6 (GPR6 belongs to Gs type) for its ability to elicit specific signaling and behavioral responses. The information derived from this project will allow us to establish an entirely new strategy to bypass the lack of endogenous ligand to specifically activate orphan GPCRs in defined cells for functional investigation of orphan receptors, facilitating the discovery of novel orphan GPCR-targeting drugs.