Transport function of the naturally occurring pathogenic polycystin-2 mutant, R742X

Most patients with autosomal dominant polycystic kidney disease (ADPKD) har bor mutations truncating polycystin-1 (PC1) or polycystin-2 (PC2), products of the PKD1 and PKD2 genes, respectively. A third member of the polycystin family, polycystin-L (PCL), was recently shown to function as a Ca2+-modul ated nonselective cat ion channel. More recently, PC2 was also shown to be a nonselective cation channel with comparable properties to PCL, though the membrane targeting of PC2 likely varies with cell types. Here we show that PC2 expressed heterologously in Xenopus oocytes is targeted to intracellul ar compartments. By contrast, a truncated form of mouse PC2 corresponding t o a naturally occurring human mutation R742X is targeted predominantly to t he plasma membrane where it mediates K+, Na+, and Ca2+ currents. Unlike PCL , the truncated form does not display Ca2+ activated transport activities, possibly due to loss of an EF-hand at the C-terminus. We propose that PC2 f orms ion channels utilizing structural components which are preserved in th e R742X form of the protein. Implications for epithelial cell signaling are discussed. (C) 2001 Academic Press.