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

Journal of cell science 2020 Dec 24

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Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD2PKD2 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. © 2020. Published by The Company of Biologists Ltd.

Citation

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. Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease. Journal of cell science. 2020 Dec 24;133(24)