Polycystin-2 Ion Channel Function and Pathogenesis in Autosomal Dominant Polycystic Kidney
10.16476/j.pibb.2022.0546
- VernacularTitle: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
- Author:
Kai WANG
1
;
Yuan HUANG
1
;
Ce-Fan ZHOU
1
;
Jing-Feng TANG
1
;
Xing-Zhen CHEN
1
Author Information
1. National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan 430068, China
- Publication Type:Journal Article
- Keywords:
polycystin-2;
ion channel;
Ca2+;
ADPKD
- From:
Progress in Biochemistry and Biophysics
2024;51(1):47-58
- CountryChina
- Language:Chinese
-
Abstract:
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 functional roles of PC2 highlight its critical importance in the pathogenesis of ADPKD, making it a promising target for therapeutic intervention.
