多囊蛋白2离子通道功能及在常染色体显性多囊肾发病中的作用机制  

Polycystin-2 Ion Channel Function and Pathogenesis in Autosomal Dominant Polycystic Kidney

作　　者：汪凯 黄渊 周策凡 唐景峰[1,2,3,4] 陈兴珍[1,2,3,4] WANG Kai;HUANG Yuan;ZHOU Ce-Fan;TANG Jing-Feng;CHEN Xing-Zhen(National“111”Center for Cellular Regulation and Molecular Pharmaceutics,Hubei University of Technology,Wuhan 430068,China;Key Laboratory of Fermentation Engineering(Ministry of Education),Hubei University of Technology,Wuhan 430068,China;Cooperative Innovation Center of Industrial Fermentation(Ministry of Education&Hubei Province),Hubei University of Technology,Wuhan 430068,China;Hubei Key Laboratory of Industrial Microbiology,Hubei University of Technology,Wuhan 430068,China)

机构地区：[1]湖北工业大学,科技部/教育部细胞调控与分子药物学科“111”引智基地,武汉430068 [2]湖北工业大学,发酵工程教育部重点实验室,武汉430068 [3]湖北工业大学,工业发酵省部共建协同创新中心,武汉430068 [4]湖北工业大学,工业微生物湖北省重点实验室,武汉430068

出　　处：《生物化学与生物物理进展》2024年第1期47-58,共12页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(31871176,32000797)资助项目。

摘　　要：多囊蛋白2 (polycystin-2,PC2,或称TRPP2,PKD2)是一种瞬时受体电位通道(transient receptor potential channel,TRP),在维持细胞正常的Ca~(2+)信号传导中起着关键作用,也是最常见的单基因常染色体显性遗传多囊肾病(transient receptor potential channel,ADPKD)的潜在病因之一。PC2可自身组装为同源四聚体离子通道或与其他蛋白质形成异源受体-离子通道复合物,参与调节机械感觉、细胞极性、细胞增殖和凋亡等多种生理功能,导致囊性细胞从正常的吸收、静止状态转变为病理性分泌、增殖状态。本文阐述了PC2蛋白相关结构域以及通道特性在维持细胞内Ca~(2+)信号传导中的关键作用,并总结了PC2在细胞膜、纤毛、内质网以及线粒体等特定亚细胞定位形成多囊蛋白复合物,参与多种细胞分化、增殖、存活和凋亡相关信号通路,为确定特异性的有效的ADPKD干预治疗途径和靶点药物提供新的思考方向。Polycystin-2(also known as PC2,TRPP2,PKD2)is a major contributor to the underlying etiology of autosomal dominant polycystic kidney disease(ADPKD),which is the most prevalent monogenic kidney disease in the world.As a transient receptor potential(TRP)channel protein,PC2 exhibits cation-permeable,Ca2+-dependent channel properties,and plays a crucial role in maintaining normal Ca2+signaling in systemic physiology,particularly in ADPKD chronic kidney disease.Structurally,PC2 protein consists of six transmembrane structural domains(S1-S6),a polycystin-specific“tetragonal opening for polycystins”(TOP)domain located between the S1 and S2 transmembrane structures,and cytoplasmic N-and C-termini.Although the cytoplasmic N-terminus and C-terminus of PC2 may not be significant in the gating of PC2 channels,there is still much protein structural information that needs to be thoroughly investigated,including the regulation of channel function and the assembly of homotetrameric ion channels.This is further supported by the presence of human disease-associated mutation sites on the PC2 structure.Moreover,PC2 synthesized in the endoplasmic reticulum is enriched in specific subcellular localization via membrane transport and can assemble itself into homotetrameric ion channels,as well as form heterotrimeric receptor-ion channel complexes with other proteins.These complexes are involved in a wide range of physiological functions,including the regulation of mechanosensation,cell polarity,cell proliferation,and apoptosis.In particular,PC2 assembles with chaperone proteins to form polycystic protein complexes that affect Ca2+transport in cell membranes,cilia,endoplasmic reticulum,and mitochondria,and are involved in activating cell fate-related signaling pathways,particularly cell differentiation,proliferation,survival,and apoptosis,and more recently,autophagy.This leads to a shift of cystic cells from a normal uptake,quiescent state to a pathologically secreted,proliferative state.In conclusion,the complex structural and functi

关 键 词：多囊蛋白2 离子通道 钙离子 常染色体显性遗传多囊肾病 

分 类 号：Q51[生物学—生物化学] R363[医药卫生—病理学]