Details

Autor(en) / Beteiligte

• Wang, Zhifei
• Ng, Courtney
• Liu, Xiong
• Wang, Yan
• Li, Bin
• Kashyap, Parul
• Chaudhry, Haroon A
• Castro, Alexis
• Kalontar, Enessa M
• Ilyayev, Leah
• Walker, Rebecca
• Alexander, R Todd
• Qian, Feng
• Chen, Xing‐Zhen
• Yu, Yong

Titel

The ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex

Ist Teil von

• EMBO reports, 2019-11, Vol.20 (11), p.e48336-n/a

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 gene, encoding the polycystic kidney disease protein polycystin‐1 and the transient receptor potential channel polycystin‐2 (also known as TRPP2), respectively. Polycystin‐1 and polycystin‐2 form a receptor–ion channel complex located in primary cilia. The function of this complex, especially the role of polycystin‐1, is largely unknown due to the lack of a reliable functional assay. In this study, we dissect the role of polycystin‐1 by directly recording currents mediated by a gain‐of‐function (GOF) polycystin‐1/polycystin‐2 channel. Our data show that this channel has distinct properties from that of the homomeric polycystin‐2 channel. The polycystin‐1 subunit directly contributes to the channel pore, and its eleven transmembrane domains are sufficient for its channel function. We also show that the cleavage of polycystin‐1 at the N‐terminal G protein‐coupled receptor proteolysis site is not required for the activity of the GOF polycystin‐1/polycystin‐2 channel. These results demonstrate the ion channel function of polycystin‐1 in the polycystin‐1/polycystin‐2 complex, enriching our understanding of this channel and its role in ADPKD. Synopsis Mutations in polycystin‐1 (PC1) or polycystin‐2 (PC2) cause autosomal dominant polycystic kidney disease. The analysis of a gain‐of‐function mutant of the PC1/PC2 ion channel provided evidence for a role of PC1 in this channel. Mutating two lower gate residues of PC2 causes the PC1/PC2 channel to be constitutively open in the plasma membrane of Xenopus oocytes. The gain‐of‐function (GOF) PC1/PC2 heterotetramer channel has larger pore and greater Ca2+ permeability than the PC2 homotetramer channel. Both PC1 and PC2 subunits are directly involved in forming the pore of the PC1/PC2 heterotetramer channel. Cleavage of PC1 at the N‐terminal G‐protein Coupled Receptor Proteolytic Site (GPS) is not a prerequisite for channel activity of the GOF PC1/PC2 channel. However, the C‐terminal GPS‐cleavage product of PC1 (PC1‐CTF) is sufficient for the activity. Mutations in polycystin‐1 (PC1) or polycystin‐2 (PC2) cause autosomal dominant polycystic kidney disease. The analysis of a gain‐of‐function mutant of the PC1/PC2 ion channel provided evidence for a role of PC1 in this channel.