The Wnt Proteins Induce Ca2+ Signaling Through The Activation Of The Polycystin Complex

WNT ligands can induce Ca2+ signaling on target cells. PKD1 (Polycystin 1) is an atypical G protein coupled receptor complexed with TRPP2 (Polycystin 2 or PKD2), a Ca2+-permeable ion channel. Inactivating mutations in the PKD1 or PKD2 genes cause autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases of unknown mechanism. Here, we show that secreted WNTs specifically bind to the extracellular domain of PKD1 and induce large whole cell currents and Ca2+ influx. Pathogenic PKD1 or PKD2 mutations that abrogate complex formation, compromise cell surface expression of PKD1, or diminish TRPP2 channel activity suppress activation by a WNT protein. Cells derived from Pkd2-/- mice show complete loss of WNT-induced Ca2+ currents and are unable to polarize in response to WNT-induced cell migration. These data define PKD1 as a new class of WNT (co)receptors coupled to Ca2+ signaling and directly implicate defective WNT/Ca2+ pathway as the primary cause of ADPKD.