1. A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts
- Author
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Tina Stumpp, Stefan Somlo, Magdalena M. Mair, Ralph Witzgall, Denise Schmied, Michael Schober, Christoph Korbmacher, Marion Kubitza, Uwe de Vries, Melanie Grosch, Markus Moser, Alexandr V. Ilyaskin, Kerstin N. Schmidt, Thaissa Dantas Pessoa, M. Gregor Madej, Karl Kunzelmann, Tobias Staudner, Helga Othmen, Katrin Brunner, Silke Haerteis, Larissa Osten, and Christine Ziegler
- Subjects
TRPP Cation Channels ,PKD2 ,Mutant ,Autosomal dominant polycystic kidney disease ,Xenopus ,Receptors, Cell Surface ,Biology ,Lumen formation ,urologic and male genital diseases ,Transient receptor potential channel ,Mice ,Tubular diameter ,Polycystic kidney disease ,medicine ,Knock-in mice ,Animals ,Homology modeling ,education ,Polycystin-2 ,Ion channel ,education.field_of_study ,urogenital system ,Cysts ,Cell Biology ,Cell Biology and Disease ,medicine.disease ,biology.organism_classification ,Autosomal-dominant polycystic kidney disease ,Polycystic Kidney, Autosomal Dominant ,female genital diseases and pregnancy complications ,Cell biology ,ddc ,Electrophysiology ,Polycystin 2 ,Kidney Tubules ,embryonic structures ,Calcium Channels ,Xenopus laevis oocytes ,Research Article ,Signal Transduction - 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., Summary: Replacement of the pore region of polycystin-2 with that of polycystin-2L1 results in wider renal tubules and polycystic kidney disease, thus demonstrating the essential function of its ion channel properties.
- Published
- 2021