Polycystin-1 loss-of-function is directly linked to an imbalance in G-Protein signaling in the kidney

The development of the kidney relies on the establishment and maintenance of a precise tubular diameter of its functional units, the nephrons. This process is disrupted in Polycystic Kidney Disease (PKD) resulting in dilations of the nephron and renal cyst formation. In the course of exploring G-protein coupled signaling in the Xenopus pronephric kidney we discovered that loss of the G-protein alpha subunit Gnas results in a PKD phenotype. Polycystin-1, one of the genes mutated in human PKD, encodes for a protein resembling a G-protein coupled receptor. Furthermore, deletion of the G-protein binding domain present in the intracellular C-terminus of Polycystin-1 impacts functionality. A comprehensive analysis of all the G-protein alpha subunits expressed in the Xenopus pronephric kidney demonstrates that Polycystin-1 recruits a select subset of G-protein alpha subunits and that their knockdown - like in the case of Gnas - results in a PKD phenotype. Mechanistically, the phenotype is caused by increased endogenous G-protein beta/gamma signaling and can be reversed by pharmacological inhibitors as well as knocking down Gnb-1. Together, our data support the hypothesis that G-proteins are recruited to the intracellular domain of PKD1 and that this interaction is critical for its function in the kidney.