Potentiation of [BK.sub.Ca] channels by cystic fibrosis transmembrane conductance regulator correctors VX-445 and VX-121

Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, ultimately leading to diminished transepithelial anion secretion and mucociliary clearance. CFTR correctors are therapeutics that restore the folding/trafficking of mutated CFTR to the plasma membrane. The large- conductance calcium-activated potassium channel ([BK.sub.Ca], [K.sub.Ca]1.1) is also critical for maintaining lung airway surface liquid (ASL) volume. Here, we show that the class 2 (C2) CFTR corrector VX-445 (elexacaftor) induces [K.sup.+] secretion across WT and F508del CFTR primary human bronchial epithelial cells (HBEs), which was entirely inhibited by the [BK.sub.Ca] antagonist paxilline. Similar results were observed with VX-121, a corrector under clinical evaluation. Whole-cell patch-clamp recordings verified that CFTR correctors potentiated [BK.sub.Ca] activity from both primary HBEs and HEK cells stably expressing the a subunit (HEK-BK cells). Furthermore, excised patch-clamp recordings from HEK-BK cells verified direct action on the channel and demonstrated a significant increase in open probability. In mouse mesenteric artery, VX-445 induced a paxilline- sensitive vasorelaxation of preconstricted arteries. VX-445 also reduced firing frequency in primary rat hippocampal and cortical neurons. We raise the possibilities that C2 CFTR correctors gain additional clinical benefit by activation of [BK.sub.Ca] in the lung yet may lead to adverse events through [BK.sub.Ca] activation elsewhere.
Introduction Cystic fibrosis (CF) affects approximately 40,000 individuals in the United States and approximately 100,000 people worldwide (1, 2). The pathogenesis of CF is the result of mutations to the [...]