Autosomal-dominant polycystic kidney disease (ADPKD) is life-threatening disease that leads to the formation of cysts in the kidneys and results ultimately in end-stage renal disease. ADPKD is caused by mutations in either polycystin 1 (PKD1) or polycystin 2 (PKD2); however, the molecular mechanisms underlying cyst formation in PKD1- or PKD2-deficient renal epithelia are not well understood. It has been proposed that PKD1 has structural similarities to the G-protein-coupled receptors (GPCRs), but the crosstalk between PKD1 and G-proteins during kidney development and disease are largely unknown. Now, Oliver Wessely and colleagues show that PKD1 directly binds to a subset of G-protein α subunits and prevents them from interacting with other GPCRs. The authors perform a systematic knockdown of all G-protein α subunits in Xenopus and identify a subset of proteins that can cause a PKD phenotype. Surface plasmon resonance analysis reveals a high binding affinity between PKD1 and four Xenopus G-protein α subunits, Gnas, Gna14, Gnai1 and Gnai2, as well as mouse Gna12. Interestingly, the authors demonstrate through comprehensive signalling pathway analyses that PKD1 functions not as a GPCR but rather as a sink for trimeric G-proteins, and that loss of Pkd1 results in hyperactivation of G-protein signalling. Taken together, these findings shed light on the mechanistic role of PKD1 in ADPKD and suggest there may be value in novel pharmacological approaches for ADPKD treatment that directly target signalling by trimeric G-protein subunits.