Abstract
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.
Highlights
Polycystic kidney disease (PKD) proteins and transient receptor potential (TRP) polycystin (TRPP) proteins form receptor/ion channel protein complexes, playing diverse roles in sensory systems [1,2]
The PKD protein polycystin-1 (PC1) and TRPP protein polycystin-2 (PC2) form a complex, which is localized on primary cilia of renal epithelial cells and is essential for renal tubular differentiation [2]
Channel current mediated by the PC1/PC2 complex has been previously reported in several experimental systems [9,60,61], replication has been inconsistent [20,40]
Summary
Polycystic kidney disease (PKD) proteins and transient receptor potential (TRP) polycystin (TRPP) proteins form receptor/ion channel protein complexes, playing diverse roles in sensory systems [1,2]. Mutations in PKD1 account for ~80% of clinically identified cases, which are usually more severe than those caused by mutations in PKD2 [6]. How these mutations lead to ADPKD is unclear, and the molecular mechanism of the function of the PC1/PC2 complex is largely unknown. It is generally believed that in the PC1/PC2 complex, PC1 functions as a receptor to sense unknown extracellular stimuli, such as mechanical force or chemical ligands, and couples it with intracellular signaling through Ca2+ influx conducted by the PC2 channel [1,2,7,8]. The Ca2+ conductance by PC2 or PC1/PC2 complex is hotly debated [7,9,10,11,12,13,14,15,16]
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