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

Thuy N. Vien, Leo C.T. Ng, Jessica M. Smith, Ke Dong, Matteus Krappitz, Vladimir G. Gainullin, Sorin Fedeles, Peter C. Harris, Stefan Somlo, Paul G. DeCaen

Research output: Contribution to journalArticlepeer-review

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 polycystin-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 that additional Ca2+-binding sites within polycystin-2 or Ca2+-dependent modifiers are responsible for regulating channel activity.

Original languageEnglish (US)
Article numberjcs255562
JournalJournal of cell science
Volume133
Issue number24
DOIs
StatePublished - Dec 2020

Keywords

  • ADPKD
  • Biophysics
  • Ca regulation
  • Ion channels
  • Polycystin
  • Primary cilia

ASJC Scopus subject areas

  • Cell Biology

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