Human Aging Research Institute (HARI), School of Life Sciences, Nanchang University, Nanchang, Jiangxi 330031, China.
School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330031, China.
Sci Adv. 2019 Jul 24;5(7):eaaw7935. doi: 10.1126/sciadv.aaw7935. eCollection 2019 Jul.
The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-Å resolution cryo-electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.
瞬时受体电位经典亚家族成员 5（TRPC5）是七种类固醇 TRPC 成员之一，是一种非选择性钙通透阳离子通道。TRPC5 作为治疗进行性肾病、抑郁症和焦虑症的药物靶点引起了相当大的兴趣。在这里，我们呈现了 2.8Å 分辨率的冷冻电镜（cryo-EM）结构的小鼠 TRPC5（mTRPC5）同源四聚体。将 TRPC5 结构与先前确定的其他 TRPC 和 TRP 通道结构进行比较，揭示了细胞外孔域和 S3 螺旋长度的差异。孔的细胞外侧的二硫键和前面的小环是其正常功能的必需元素。mTRPC5 的这种高分辨率结构，结合电生理学和突变分析，为理解 TRPC 家族离子通道的脂质调节和门控机制提供了线索。
