{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:54:22Z","timestamp":1790049262494,"version":"4.0.1"},"reference-count":46,"publisher":"American Physiological Society","issue":"4","funder":[{"DOI":"10.13039\/100004090","name":"Christopher Ricardo Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["BRIDGE18XXO"],"award-info":[{"award-number":["BRIDGE18XXO"]}],"id":[{"id":"10.13039\/100004090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["DEVOR20GO"],"award-info":[{"award-number":["DEVOR20GO"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2022,10,1]]},"abstract":"<jats:p> We previously identified potentiators of KCa3.1 (5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one; DCEBIO) that stimulate Cl<jats:sup>\u2212<\/jats:sup> secretion across human bronchial epithelial cells (HBEs) expressing wild-type (WT) cystic fibrosis transmembrane conductance regulator (CFTR). However, these compounds failed to stimulate Cl<jats:sup>\u2212<\/jats:sup> secretion in F508del CFTR HBEs. Drug discovery efforts identified CFTR potentiators (VX-770) and correctors (VX-445, VX-661) for cystic fibrosis (CF) disease-causing mutations, including F508del and G551D. Herein, we evaluated the effect of KCa3.1 potentiation on Cl<jats:sup>\u2212<\/jats:sup> equivalent current (I<jats:sub>Cl<\/jats:sub>) across primary HBEs expressing WT, F508del, and G551D CFTR. Transepithelial impedance analysis was used to obtain estimates of apical (R<jats:sub>a<\/jats:sub>) and basolateral membrane (BLM; R<jats:sub>b<\/jats:sub>) resistances. In WT CFTR HBEs, DCEBIO stimulated I<jats:sub>Cl<\/jats:sub>, which was increased by forskolin. Similarly, forskolin stimulated I<jats:sub>Cl<\/jats:sub>, and this was increased by DCEBIO. The KCa3.1 blocker, TRAM-34 inhibited I<jats:sub>Cl<\/jats:sub>. DCEBIO decreased R<jats:sub>b<\/jats:sub>, whereas TRAM-34 increased R<jats:sub>b<\/jats:sub>, consistent with BLM localization of KCa3.1. Following correction of F508del CFTR with VX-445\u2009+\u2009VX-661, DCEBIO failed to stimulate I<jats:sub>Cl<\/jats:sub>, although the subsequent addition of forskolin\u2009+\u2009VX-770 increased I<jats:sub>Cl<\/jats:sub>. Importantly, following stimulation of I<jats:sub>Cl<\/jats:sub> with forskolin\u2009+\u2009VX-770, DCEBIO induced a further significant increase in I<jats:sub>Cl<\/jats:sub>. As above, DCEBIO reduced R<jats:sub>b<\/jats:sub>, whereas TRAM-34 increased R<jats:sub>b<\/jats:sub>, consistent with BLM localized KCa3.1. Finally, we assessed KCa3.1 potentiation on I<jats:sub>Cl<\/jats:sub> in G551D\/F508del CFTR HBEs in the absence or presence of VX-445\u2009+\u2009VX-661. In both cases, DCEBIO failed to stimulate I<jats:sub>Cl<\/jats:sub>. However, following stimulation with forskolin\u2009+\u2009VX-770, DCEBIO nearly doubled I<jats:sub>Cl<\/jats:sub>. Our results demonstrate that following correction\/potentiation of F508del and G551D CFTR, potentiation of KCa3.1 increases the Cl<jats:sup>\u2212<\/jats:sup> secretory response, suggesting this class of compounds may represent a novel means of further increasing Cl<jats:sup>\u2212<\/jats:sup> secretion across CF airway. <\/jats:p>","DOI":"10.1152\/ajpcell.00319.2022","type":"journal-article","created":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T11:29:53Z","timestamp":1662377393000},"page":"C1215-C1230","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["KCa3.1 potentiation stimulates Cl<sup>\u2212<\/sup> secretion in F508del and G551D CFTR-corrected primary human bronchial epithelial cells"],"prefix":"10.1152","volume":"323","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3013-5179","authenticated-orcid":false,"given":"Daniel C.","family":"Devor","sequence":"first","affiliation":[{"name":"Department of 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