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ResearchIn-Press PreviewTherapeutics
Open Access | 10.1172/JCI176328
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by Kolski-Andreaco, A. in: JCI | PubMed | Google Scholar
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by Taiclet, S. in: JCI | PubMed | Google Scholar
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by Myerburg, M. in: JCI | PubMed | Google Scholar
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by sembrat, j. in: JCI | PubMed | Google Scholar
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by Bridges, R. in: JCI | PubMed | Google Scholar
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by Straub, A. in: JCI | PubMed | Google Scholar
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by Wills, Z. in: JCI | PubMed | Google Scholar
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by Butterworth, M. in: JCI | PubMed | Google Scholar
1Department of Cell Biology, University of Pittsburgh, Pittsburgh, United States of America
2Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States of America
3MUH NW 625, University of Pittsburgh, Pittsburgh, United States of America
4Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh, Pittsburgh, United States of America
5Dept of Physiology and Biophysics, Chicago Medical School, North Chicago, United States of America
6Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States of America
Find articles by Devor, D. in: JCI | PubMed | Google Scholar
Published July 2, 2024 - More info
Cystic fibrosis (CF) results from mutations in the 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 BKCa potassium channel is also critical for maintaining lung ASL volume. Here, we show the CFTR corrector, VX-445 (Elexacaftor), a component of Trikafta, 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 confirmed potentiated channel activity from CFTR correctors on the BKCa α-subunit, and excised patch-clamp recordings demonstrated a significant increase in open probability. In mesenteric artery, VX-445 induced a paxilline-sensitive vasorelaxation of preconstricted arteries. VX-445 also reduced action potential firing frequency in primary hippocampal and cortical neurons. VX-445 effects were observed at low micomolar concentrations (1-10 µM) – within the range reported in plasma and tissues from CF patients. We raise the possibilities that CFTR correctors gain additional clinical benefit by activation of BKCa in the lung, yet may lead to adverse events through BKCa activation, elsewhere.