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Disrupting Polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease.

Authors
  • Vien, Thuy N1
  • Ng, Leo C T1
  • Smith, Jessica M2
  • Dong, Ke3
  • Krappitz, Matteus3
  • Gainullin, Vladimir G2
  • Fedeles, Sorin3
  • Harris, Peter C2
  • Somlo, Stefan3
  • DeCaen, Paul G4
  • 1 Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 2 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
  • 3 Departments of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 4 Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA [email protected]
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Nov 16, 2020
Identifiers
DOI: 10.1242/jcs.255562
PMID: 33199522
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD2 PKD2 encodes polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca2+ modulates polycystin-2 voltage dependent gating and subsequent desensitization- two biophysical regulatory mechanisms that control its function at physiological membrane potentials. Here, we refute the hypothesis that Ca2+ occupancy of the polycytsin-2 intracellular EF hand is responsible for these forms of channel regulation, and if disrupted, results in ADPKD. We identify and introduce mutations that attenuate Ca2+-EF hand affinity but find channel function is unaltered in the primary cilia and ER membranes. We generated two new mouse strains that harbor distinct mutations that abolish Ca2+-EF hand association but do not result in a PKD phenotype. Our findings suggest additional Ca2+ binding sites within polycystin-2 or Ca2+-dependent modifiers are responsible for regulating channel activity. © 2020. Published by The Company of Biologists Ltd.

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