Cleveland Clinic Foundation, Lerner Research Institute, Department of Cellular and Molecular Medicine, 9500 Euclid Avenue/NC10, Cleveland, OH 44195, USA.
LSU Health Sciences Center, Department of Cell Biology and Anatomy, 1901 Perdido Street, New Orleans, LA 70112, USA.
Development. 2018 Mar 22;145(6):dev158931. doi: 10.1242/dev.158931.
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 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 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.
肾脏的发育依赖于其功能单位——肾单位的精确管状直径的建立和维持。这个过程在多囊肾病（PKD）中被打乱，导致肾单位扩张和肾囊肿形成。在探索前肾中的 G 蛋白偶联信号的过程中，我们发现 G 蛋白α亚基 Gnas 的缺失会导致 PKD 表型。多囊蛋白 1 是人类 PKD 突变的基因之一，它编码一种类似于 G 蛋白偶联受体的蛋白质。此外，缺失多囊蛋白 1 胞内 C 端存在的 G 蛋白结合域会影响其功能。对前肾中表达的所有 G 蛋白α亚基的综合分析表明，多囊蛋白 1 募集了一组特定的 G 蛋白α亚基，其敲低——就像 Gnas 一样——会导致 PKD 表型。从机制上讲，这种表型是由内源性 G 蛋白β/γ信号的增加引起的，可被药理学抑制剂以及敲低 Gnb1 逆转。总之，我们的数据支持这样一种假设，即 G 蛋白被招募到 PKD1 的细胞内结构域，这种相互作用对其在肾脏中的功能至关重要。
