TRPC通道的结构机制研究进展  

Advances in the structural mechanism of TRPC channels

作　　者：郭文君[1] 陈雷[1] Wenjun Guo;Lei Chen(College of Future Technology,Institute of Molecular Medicine,National Biomedical Imaging Center,Peking University,State Key Laboratory of Membrane Biology,Beijing Key Laboratory of Cardiometabolic Molecular Medicine,Beijing 100871,China)

机构地区：[1]北京大学未来技术学院,分子医学研究所,代谢及心血管分子医学北京市重点实验室,国家生物医学成像科学中心,膜生物学国家重点实验室,北京100871

出　　处：《科学通报》2023年第17期2213-2220,共8页Chinese Science Bulletin

基　　金：国家杰出青年科学基金(32225027)资助。

摘　　要：经典型瞬时受体电势通道(transient receptor potential canonical channel,TRPC)是一类重要的非选择性阳离子通道.该通道家族包含多个成员,在体内广泛分布,参与多种生理病理过程,是治疗如局灶节段性肾小球硬化症(focal segmental glomerular sclerosis,FSGS)等疾病的药物靶点.得益于单颗粒冷冻电子显微镜技术的快速发展,目前已解析的TRPC通道家族多个成员的结构展示了TRPC通道四聚体的组装模式、各结构域的空间排布、具有调节功能的钙离子结合位点和多种小分子化合物的作用位点.这些结构信息与功能实验相辅相成,共同揭示了TRPC通道被钙离子双向调节的机制、小分子化合物的作用机制,以及在人类遗传疾病中发现的致病突变体的激活机制.这些研究进展为进一步探索TRPC通道的工作原理和靶向TRPC通道的药物开发提供了坚实的基础.Transient receptor potential canonical channels(TRPCs) are calcium-permeable,nonselective cation channels.Human TRPC channels contain six functional members:TRPC1,and TRPC3-7,and they are widely distributed in many tissues.These channels are involved in numerous physiological processes,including regulating myogenic tone and blood pressure,endothelial barrier function regulation,hypoxic pulmonary vasoconstriction,neuronal function,and kidney function.They are also associated with several diseases,including traumatic brain injury,pathologic cardiac hypertrophy,atherosclerosis,the development of cancer,and diabetes.Specifically,gain-of-function mutations of the TRPC6 gene in humans cause focal segmental glomerular sclerosis(FSGS),a chronic kidney disease for which there is no effective treatment.Consequently,TRPC channels serve as drug targets for several diseases,including FSGS and anxiety.Recent developments in singleparticle cryo-EM permit the determination of the structures of multiple TRPC channel members(TRPC3,TRPC4,TRPC5,and TRPC6) in multiple states at near-atomic resolutions.These structures demonstrate that TRPC channels are tetramers composed of two layers:The upper transmembrane domain(TMD) and the lower intracellular domain(ICD).The ICD layer consists of ankyrin repeat domains(ARD),linker helices domains(LHD),the TRP helix,and C terminal helices.The four protomers' voltage sensor-like domains(VSLD) and pore domains form the TMD layer.ICD has a bell-like shape with a large central chamber and caps below TMD.The structures reveal both the inhibitory calcium binding site in ICD and the activating calcium binding site in TMD.Calcium binding to the inhibitory site results in the closure of the ICD and the restriction of ion flow through the ICD,whereas calcium dissociation from the inhibitory site results in the opening of the ICD and the unrestricted flow of ions through the ICD.Calcium binding to the activating site increases its activity.Additionally,the binding pockets and binding poses of several small

关 键 词：TRPC通道 单颗粒冷冻电子显微镜 慢性肾病 局灶节段性肾小球硬化症 

分 类 号：R692[医药卫生—泌尿科学]