新型抗抑郁药物靶点TRPC5离子通道的结构药理学研究

抑郁症是我国最严重的精神疾病之一，但是现有的抗抑郁药物起效较慢并且有一定的副作用。因此，开发安全、疗效更好和起效快的抗抑郁药物尤为重要。研究表明，敲除TRPC5基因会使小鼠对于恐惧诱导分子-胆囊收缩素的反应减弱。同时，使用TRPC5的拮抗剂能够明显减少小鼠在迷宫中的焦虑行为。因此，TRPC5是非常具有潜力的治疗抑郁症药物靶点。前期，我们对于瞬时受体电位（TRP）离子通道家族的蛋白做了系统的研究（Nature Communications, 2018）(PNAS, 2018）。本项目我们将对新型抗抑郁药物靶点TRPC5进行结构药理学研究。主要目标如下: 1) 解析TRPC5与小分子化合物复合物结构; 2) 解析TRPC5与激动剂的复合物结构，阐明TRPC5的激活机制; 3）基于TRPC5结构进行小分子化合物的筛选。该研究将促进新型抗抑郁药物开发和加深人们对于TRPC离子通道生理功能的理解。

Depression is one of the most serious mental disorders in our country, but existing drugs for depression frequently have undesirable side effects and the delayed onset of antidepressant effect. Therefore, there is definitely a need for the development of new antidepressant drugs with superior efficacy and safety as well as an earlier onset of action. Previous studies have demonstrated that TRPC5-null mice show attenuated responses to the panic-inducing agent cholecystokinin tetrapeptide. In addition, anxiety behaviors are reduced in maze by the treatment with a TRPC5 antagonist. Therefore, TRPC5 has a great potential to be a new drug target in treating depression. In our previous studies, we have systematically studied the structural pharmacology of the Transient Receptor Potential ion channel family（Nature Communications, 2018）(PNAS, 2018). In this project, we will study the structural pharmacology of the novel antidepressant drug target TRPC5. In Aim 1, we will elucidate the high-resolution structures of TRPC5 bound to different small molecule compounds. We will then solve the structure of TRPC5-agonist complex and elucidate the activation mechanism of TRPC5 (Aim 2). Finally (Aim 3), we will screen small molecule compounds based on the structures of TRPC5. Our studies will not only facilitate the development of new antidepressant drugs but also provide a better understanding of the physiological function of the biologically important TRPC ion channels.