Holding open the door reveals a new view of polycystin channel function

Abstract

The functions of polycystin 1 and polycystin 2 (PC1 and PC2) have been surprisingly difficult to establish. PC1 and PC2 are encoded by the Pkd1 and Pkd2 genes that are implicated in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is the most common potentially lethal genetic disorder, affecting ~1 in 1,000 people. Over the course of decades, ADPKD patients’ kidneys acquire numerous fluid‐filled cysts whose expansion compresses the surrounding parenchyma, leading to end‐stage renal disease in ~50% of afflicted individuals [1]. Identification of the genes encoding the PC proteins 20 years ago led to the hypothesis that they form an ion channel, since the sequence of PC2 marks it as a member of the TRP family of cation channels. In the ensuing 2 decades, tremendous effort has been devoted to determining whether this is indeed true and, if so, what characteristics that channel might manifest. A recent paper by Wang et al in this issue of EMBO Reports [2] demonstrates that assembly with PC1 changes the properties of the polycystin channel in ways that may help explain the complex behaviors that have been attributed to it. A study in this issue provides evidence that PC1 functions as an ion channel pore‐forming subunit in the PC1/PC2 complex. The assembly with PC1 changes the channel properties compared to PC2 homotetrameric channels.