Open AccessDisrupting Polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease
Author(s) -
Thuy N. Vien,
Leo C.T. Ng,
Jessica M. Smith,
Ke Dong,
Matteus Krappitz,
Vladimir G. Gainullin,
Sorin V. Fedeles,
Peter C. Harris,
Stefan Somlo,
Paul G. DeCaen
Publication year - 2020
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.255562
Subject(s) - biology , polycystic kidney disease , function (biology) , disease , polycystic kidney , microbiology and biotechnology , medicine , endocrinology , kidney
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 Ca 2+ 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 Ca 2+ 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 Ca 2+ -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 Ca 2+ -EF hand association but do not result in a PKD phenotype. Our findings suggest that additional Ca 2+ -binding sites within polycystin-2 or Ca 2+ -dependent modifiers are responsible for regulating channel activity.