A Polycystin-2 Protein with Modified Channel Properties Leads to an Increased Diameter of Renal Tubules and to Renal Cysts

Overview

Journal J Cell Sci

Specialty Cell Biology

Date 2021 Aug 4

PMID 34345895

Citations 1

Authors

Melanie Grosch

Katrin Brunner

Alexandr V Ilyaskin

Michael Schober

Tobias Staudner

Denise Schmied

Tina Stumpp

Kerstin N Schmidt

M Gregor Madej

Thaissa D Pessoa

Helga Othmen

Marion Kubitza

Larissa Osten

Uwe de Vries

Magdalena M Mair

Stefan Somlo

Markus Moser

Karl Kunzelmann

Christine Ziegler

Silke Haerteis

Christoph Korbmacher

Ralph Witzgall

Affiliations

Soon will be listed here.

Abstract

Mutations in the PKD2 gene cause autosomal-dominant polycystic kidney disease but the physiological role of polycystin-2, the protein product of PKD2, remains elusive. Polycystin-2 belongs to the transient receptor potential (TRP) family of non-selective cation channels. To test the hypothesis that altered ion channel properties of polycystin-2 compromise its putative role in a control circuit controlling lumen formation of renal tubular structures, we generated a mouse model in which we exchanged the pore loop of polycystin-2 with that of the closely related cation channel polycystin-2L1 (encoded by PKD2L1), thereby creating the protein polycystin-2poreL1. Functional characterization of this mutant channel in Xenopus laevis oocytes demonstrated that its electrophysiological properties differed from those of polycystin-2 and instead resembled the properties of polycystin-2L1, in particular regarding its permeability for Ca2+ ions. Homology modeling of the ion translocation pathway of polycystin-2poreL1 argues for a wider pore in polycystin-2poreL1 than in polycystin-2. In Pkd2poreL1 knock-in mice in which the endogenous polycystin-2 protein was replaced by polycystin-2poreL1 the diameter of collecting ducts was increased and collecting duct cysts developed in a strain-dependent fashion.

Citing Articles

Disease-associated missense mutations in the pore loop of polycystin-2 alter its ion channel function in a heterologous expression system.

Staudner T, Geiges L, Khamseekaew J, Sure F, Korbmacher C, Ilyaskin A J Biol Chem. 2024; 300(8):107574.

PMID: 39009345 PMC: 11630642. DOI: 10.1016/j.jbc.2024.107574.

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