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

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

Development

Cleveland Clinic Foundation, Lerner Research Institute, Department of Cellular and Molecular Medicine, 9500 Euclid Avenue/NC10, Cleveland, OH 44195, USA

Published: March 2018

AI Article Synopsis

  • The development of nephrons in the kidney is crucial for maintaining their tubular diameter; disruption of this process leads to polycystic kidney disease (PKD), characterized by nephron dilation and cyst formation.
  • Research revealed that the loss of the G-protein α subunit Gnas induces PKD-like symptoms, highlighting its role in kidney function.
  • Findings suggest that polycystin 1, a key protein in PKD, works with specific G-protein α subunits, and interfering with these interactions can potentially reverse PKD symptoms.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897598PMC
http://dx.doi.org/10.1242/dev.158931DOI Listing

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