神经递质通过结合神经递质离子型（离子通道）受体和G蛋白偶联型受体（GPCR）传递突触连接和调节生理功能。多种神经递质结合的不同GPCR型受体都是重要的药物靶点。研究表明，GPCR可形成同源二聚体而不同GPCR可形成异源二聚体和多聚体。同源，异源二聚化或多聚化产生的受体，不仅仅是受体亚基或受体之间的组合，而是一类“新受体”。它不仅仅继承了各自母体的部分特性，同时会产生新的生理功能，这一类神经递质GPCR二聚体和多聚体将会是一类极具潜力的新的，低副作用的治疗靶点。本项目，我们将利用SNAP标记技术对几类重要的神经递质受体二聚化和多聚化进行筛选，进而选择几类代表性神经递质GPCR二聚化和多聚化药理学细节进行研究，从结构和功能的角度解析“新受体”激活的动态相互作用界面，将为神经递质GPCR二聚化或多聚化提供药理学验证和新的筛选模型，并最终开发基于其构象变化的非天然氨基酸标记的新型筛选方法。

Neurotransmitter transmit the synaptic signals and regulate physiological functions through neurotransmitters receptors such as Channel type and G protein coupled type receptors (GPCR). Most neurotransmitter GPCRs are important durg targets. Growing evidences show that GPCRs exist as dimers and oligomers. They inherit some of the characteristics from their parental receptors and more interestingly, generate new physiological functions. The neurotransmitter GPCR dimers and oligomers will be a class of novel, high potential therapeutic targets with low-side effects. In this project, we will carry on the dimerization and oligomerization screening of several important neurotransmitter receptors by using the snap-tag labeling technology and select several representative neurotransmitter GPCR dimers and oligomers to investigate their pharmacological details. We will investigate the dynamic interface within the activated “new receptors” through structure and function analyses; provide pharmacological validation of the neurotransmitter GPCR dimerization or oligomerization; and finally develop a novel screening model based on the conformational changes by using the unnatural amino acid labeling technology.