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Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator correctors VX-445 and VX-121
Aaron Kolski-Andreaco, … , Michael B. Butterworth, Daniel C. Devor
Aaron Kolski-Andreaco, … , Michael B. Butterworth, Daniel C. Devor
Published July 2, 2024
Citation Information: J Clin Invest. 2024;134(16):e176328. https://doi.org/10.1172/JCI176328.
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Research Article

Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator correctors VX-445 and VX-121

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Abstract

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 (BKCa, KCa1.1) 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+ secretion across WT and F508del CFTR primary human bronchial epithelial cells (HBEs), which was entirely inhibited by the BKCa antagonist paxilline. Similar results were observed with VX-121, a corrector under clinical evaluation. Whole-cell patch-clamp recordings verified that CFTR correctors potentiated BKCa activity from both primary HBEs and HEK cells stably expressing the α 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 BKCa in the lung yet may lead to adverse events through BKCa activation elsewhere.

Authors

Aaron Kolski-Andreaco, Stefanie Taiclet, Michael M. Myerburg, John Sembrat, Robert J. Bridges, Adam C. Straub, Zachary P. Wills, Michael B. Butterworth, Daniel C. Devor

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Figure 5

Effect of forskolin and VX-445 on BKCa currents in F508del CFTR HBEs.

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Effect of forskolin and VX-445 on BKCa currents in F508del CFTR HBEs.
(A...
(A) Subsequent to amiloride, forskolin (10 μM) stimulated a paxilline-sensitive increase in K+ secretion, which is recognized as an initial transient spike followed by a sustained increase in Isc. Addition of XE-991 (10 μM) had little effect on the remaining current. (B) Subsequent to amiloride and paxilline, forskolin (10 μM) failed to stimulate K+ secretion. (C) Following forskolin, VX-445 (10 μM) induced a further increase in K+ secretion, which was paxilline sensitive. (D) VX-445 (10 μM) stimulated a sustained increase in K+ secretory current, which was further increased by forskolin. Subsequent addition of paxilline completely inhibited this K+ secretory current. (E) Average responses (mean ± SEM) to forskolin and VX-445 either alone or after addition of the previous agonist (#P < 0.01; unpaired ANOVA). Three donors were used in these studies. Experimental replicates are indicated in parentheses above each data set.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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