VX-445 (elexacaftor) inhibits chloride secretion across human bronchial epithelial cells by directly blocking KCa3.1 channels.

Abstract

Cystic fibrosis (CF) is a genetic disorder resulting from mutations to the CF transmembrane regulator (CFTR) anion channel. CFTR correctors partially restore the folding and trafficking of mutant CFTR. We recently demonstrated that the correctors VX-445 and VX-121 directly potentiate large-conductance Ca²⁺-activated (BK_Ca) channels. We postulated that this could enhance the therapeutic potential of these drugs in the lung by increasing the driving force for transepithelial Cl^- secretion. Herein, we evaluated the effect of acute addition of VX-445 on forskolin- and 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one-mediated Cl^- secretion across primary human bronchial epithelial cells (HBEs) from wild type (WT) and F508del donors. Surprisingly, VX-445 (10 µM) induced a significant inhibition of forskolin-stimulated Cl^- secretion in WT and F508del donor HBEs with corrected CFTR. We hypothesized that this was due to inhibition of the basolateral membrane Ca²⁺-activated K⁺ channel, KCa3.1 that maintains the driving force for Cl^- secretion. Thus, we utilized patch-clamp techniques to evaluate VX-445 effects on isolated KCa3.1 currents. We demonstrate that VX-445 directly inhibits KCa3.1, as do similar molecules VX-659 and VX-121; however, only VX-659 inhibited KCa2.3 and KCa2.2 with a similar affinity to KCa3.1. To summarize, acute addition of CFTR correctors to HBEs reduces transepithelial Cl^- secretion due to inhibition of KCa3.1.