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

Abstract

<p id="d7458354e169">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 <i>Xenopus</i> pronephric kidney, we discovered that loss of the G-protein α subunit, Gnas, results in a PKD phenotype. Polycystin 1, one of the genes mutated in human PKD, encodes 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 α subunits expressed in the <i>Xenopus</i> pronephric kidney demonstrates that polycystin 1 recruits a select subset of G-protein α subunits and that their knockdown – as in the case of Gnas – results in a PKD phenotype. Mechanistically, the phenotype is caused by increased endogenous G-protein β/γ signaling and can be reversed by pharmacological inhibitors as well as knocking down Gnb1. Together, our data support the hypothesis that G proteins are recruited to the intracellular domain of PKD1 and that this interaction is crucial for its function in the kidney. </p><p class="first" id="d7458354e179"> <span class="generated">[Related article:]</span> <b>Highlighted Article:</b> Polycystin 1, which is mutated in autosomal dominant polycystic kidney disease, relies on its binding to a select class of trimeric G proteins and its loss of function results in a hyper-sensitization of co-expressed GPCRs. </p>