Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder occurring in approximately 1 in 1000 births in human, causing renal failure in 50 % of affected individuals and even deaths. In most cases, the disease arises as a consequence of mutations in either of two genes PKD1 and PKD2, which encode polycystins 1 and 2, respectively. The PKD2 family of genes has also been implicated in sensory responses through protein localization on primary cilia of epithelia and neurons and may be critical for left-right asymmetry of the body plan (situs inversus)(1) and sperm motility (2). PKD1 is a large plasma membrane protein involved in cell-cell interaction, whereas PKD2 is a Ca2+-permeable channel belonging to the TRP channel superfamily. Although PKD1 and PKD2 interact and are thought to be part a common sensory signaling pathway, little is known about the gating mechanism of these polycystin complexes. Here, we show that PKD1 and PKD2 form functionally associated ‘subunits’ of a heteromultimeric signaling complex that functions either as a Ca2+-permeable cation channel (3) or as a G-protein-coupled receptor (4). Within these complexes, PKD1 acts as a cell surface receptor that controls the gating of the PKD2 channel via a structural rearrangement. This coupling is disrupted in disease-associated mutant forms of PKD1 that are incapable of heterodimerization with PKD2.Evidence will be also presented that suggest that polycystin proteins co-assemble to form junctional ‘plasma-ERosome’ complexes in which plasmalemmal PKD1 gates intracellular PKD2 by a mechanism similar to those outlined in the conformational coupling hypotheses of excitation-contraction and store-operated channels. Thus, PKD1 acts as a prototypical membrane receptor that concordantly activates G-proteins and regulates Ca2+ transport via PKD2 channels, a bimodal mechanism that may account for the multifunctional roles of polycystin proteins in fundamental cellular processes of various cell types.