{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:53:13Z","timestamp":1790049193180,"version":"4.0.1"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["DEVOR22GO"],"award-info":[{"award-number":["DEVOR22GO"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["DEVOR23GO"],"award-info":[{"award-number":["DEVOR23GO"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["BRIDGE18XXO"],"award-info":[{"award-number":["BRIDGE18XXO"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL171413"],"award-info":[{"award-number":["HL171413"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK102843"],"award-info":[{"award-number":["DK102843"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 (BKCa) channels. We postulated that this could enhance the therapeutic potential of these drugs in the lung by increasing the driving force for transepithelial Cl\u2212 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\u2212 secretion across primary human bronchial epithelial cells (HBEs) from wild type (WT) and F508del donors. Surprisingly, VX-445 (10\u2005\u00b5M) induced a significant inhibition of forskolin-stimulated Cl\u2212 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\u2212 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\u2212 secretion due to inhibition of KCa3.1.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgaf211","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T06:36:09Z","timestamp":1751610969000},"source":"Crossref","is-referenced-by-count":6,"title":["VX-445 (elexacaftor) inhibits chloride secretion across human bronchial epithelial cells by directly blocking KCa3.1 channels"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6574-631X","authenticated-orcid":false,"given":"Aaron","family":"Kolski-Andreaco","sequence":"first","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh , 3500 Terrace St., Pittsburgh, PA 15261 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2986-1678","authenticated-orcid":false,"given":"Corina M","family":"Balut","sequence":"additional","affiliation":[{"name":"AbbVie, Inc. , ZR13, Bldg. AP9A, 1 North Waukegan Road, North Chicago, IL 60064 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0090-1848","authenticated-orcid":false,"given":"Matthew D","family":"Green","sequence":"additional","affiliation":[{"name":"AbbVie, Inc. , ZR13, Bldg. AP9A, 1 North Waukegan Road, North Chicago, IL 60064 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4108-803X","authenticated-orcid":false,"given":"John","family":"Sembrat","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine (PACCSM), University of Pittsburgh , 3500 Terrace St., Pittsburgh, PA 15213 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J","family":"Bridges","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Chicago Medical School , 3333 Green Bay Rd., North Chicago, IL 60064 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8470-0218","authenticated-orcid":false,"given":"Ashvani K","family":"Singh","sequence":"additional","affiliation":[{"name":"AbbVie, Inc. , ZR13, Bldg. AP9A, 1 North Waukegan Road, North Chicago, IL 60064 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4765-468X","authenticated-orcid":false,"given":"Chris","family":"Tse","sequence":"additional","affiliation":[{"name":"AbbVie, Inc. , ZR13, Bldg. AP9A, 1 North Waukegan Road, North Chicago, IL 60064 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B","family":"Butterworth","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh , 3500 Terrace St., Pittsburgh, PA 15261 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3013-5179","authenticated-orcid":false,"given":"Daniel C","family":"Devor","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, University of Pittsburgh , 3500 Terrace St., Pittsburgh, PA 15261 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"2025071907320322200_pgaf211-B1","author":"Cystic Fibrosis Foundation"},{"issue":"6","key":"2025071907320322200_pgaf211-B2","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.molmed.2007.05.001","article-title":"Cystic fibrosis: a disease of vulnerability to airway surface dehydration","volume":"13","author":"Boucher","year":"2007","journal-title":"Trends Mol Med"},{"key":"2025071907320322200_pgaf211-B3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1113\/jphysiol.1988.sp017322","article-title":"Evidence for reduced Cl- and increased Na+ permeability in cystic fibrosis human primary cell cultures","volume":"405","author":"Boucher","year":"1988","journal-title":"J Physiol"},{"issue":"5","key":"2025071907320322200_pgaf211-B4","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1172\/JCI112708","article-title":"Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation","volume":"78","author":"Boucher","year":"1986","journal-title":"J Clin Invest"},{"issue":"1","key":"2025071907320322200_pgaf211-B5","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1172\/JCI112812","article-title":"Abnormal apical cell membrane in cystic fibrosis respiratory epithelium. 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