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Development 2018 Mar 22;1456:. doi: 10.1242/dev.158931.
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Polycystin 1 loss of function is directly linked to an imbalance in G-protein signaling in the kidney.

Zhang B , Tran U , Wessely O .

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 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 Xenopus 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.

PubMed ID: 29530879
PMC ID: PMC5897598
Article link: Development
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: adm atp1b1 camp gna11 gna13 gna14 gna15 gnai1 gnai2 gnai3 gnal gnao1 gnaq gnas gnat1 gnat2 gnaz gnb1 gnb3 gnb4 gnb5 gprc6a myc nphs1 pkd1 pkd2 prkd1 pth rack1 rapgef4 slc12a1 slc12a3 slc4a4 slc5a9 smo spr sst.1
GO keywords: G-protein coupled receptor binding [+]
Antibodies: Gnas Ab2 Gnas Ab3
Morpholinos: gna11 MO2 gna13 MO1 gna14 MO1 gna14 MO2 gna15 MO1 gnai1 MO1 gnai2 MO1 gnai3 MO1 gnal MO1 gnaq MO1 gnas MO1 gnat1 MO1 gnb1 MO1 pkd1 MO1 pkd2 MO1 rapgef4 MO1

Disease Ontology terms: polycystic kidney disease 1 [+]

Article Images: [+] show captions
References [+] :
Avasthi, Primary Cilia in Cystic Kidney Disease. 2017, Pubmed