{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:46:20Z","timestamp":1791326780764,"version":"4.3.1"},"reference-count":50,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,5,1]]},"abstract":"<jats:p>Serous cells are the predominant site of cystic fibrosis transmembrane conductance regulator expression in the airways, and they make a significant contribution to the volume, composition, and consistency of the submucosal gland secretions. We have employed the human airway serous cell line Calu-3 as a model system to investigate the mechanisms of serous cell anion secretion. Forskolin-stimulated Calu-3 cells secrete HCO\u22123 by a Cl \u2212-independent, serosal Na+-dependent, serosal bumetanide-insensitive, and serosal 4,4\u2032-dinitrostilben-2,2\u2032-disulfonic acid (DNDS)\u2013sensitive, electrogenic mechanism as judged by transepithelial currents, isotopic fluxes, and the results of ion substitution, pharmacology, and pH studies. Similar studies revealed that stimulation of Calu-3 cells with 1-ethyl-2-benzimidazolinone (1-EBIO), an activator of basolateral membrane Ca2+-activated K+ channels, reduced HCO\u22123 secretion and caused the secretion of Cl \u2212 by a bumetanide-sensitive, electrogenic mechanism. Nystatin permeabilization of Calu-3 monolayers demonstrated 1-EBIO activated a charybdotoxin- and clotrimazole- inhibited basolateral membrane K+ current. Patch-clamp studies confirmed the presence of an intermediate conductance inwardly rectified K+ channel with this pharmacological profile. We propose that hyperpolarization of the basolateral membrane voltage elicits a switch from HCO\u22123 secretion to Cl \u2212 secretion because the uptake of HCO\u22123 across the basolateral membrane is mediated by a 4,4 \u2032-dinitrostilben-2,2\u2032-disulfonic acid (DNDS)\u2013sensitive Na+:HCO\u22123 cotransporter. Since the stoichiometry reported for Na +:HCO\u22123 cotransport is 1:2 or 1:3, hyperpolarization of the basolateral membrane potential by 1-EBIO would inhibit HCO\u22123 entry and favor the secretion of Cl \u2212. Therefore, differential regulation of the basolateral membrane K+ conductance by secretory agonists could provide a means of stimulating HCO\u22123 and Cl \u2212 secretion. In this context, cystic fibrosis transmembrane conductance regulator could serve as both a HCO\u22123 and a Cl \u2212 channel, mediating the apical membrane exit of either anion depending on basolateral membrane anion entry mechanisms and the driving forces that prevail. If these results with Calu-3 cells accurately reflect the transport properties of native submucosal gland serous cells, then HCO\u22123 secretion in the human airways warrants greater attention.<\/jats:p>","DOI":"10.1085\/jgp.113.5.743","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:50:20Z","timestamp":1027702220000},"page":"743-760","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":236,"title":["Bicarbonate and Chloride Secretion in Calu-3 Human Airway Epithelial Cells"],"prefix":"10.1085","volume":"113","author":[{"given":"Daniel C.","family":"Devor","sequence":"first","affiliation":[{"name":"From the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashvani K.","family":"Singh","sequence":"additional","affiliation":[{"name":"From the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda C.","family":"Lambert","sequence":"additional","affiliation":[{"name":"From the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"DeLuca","sequence":"additional","affiliation":[{"name":"From the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond A.","family":"Frizzell","sequence":"additional","affiliation":[{"name":"From the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Bridges","sequence":"additional","affiliation":[{"name":"From the Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1999,5,1]]},"reference":[{"key":"2023072918182590700_B1","doi-asserted-by":"crossref","first-page":"17689","DOI":"10.1074\/jbc.273.28.17689","article-title":"Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter","volume":"273","author":"Abuladze","year":"1998","journal-title":"J Biol Chem"},{"key":"2023072918182590700_B2","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1113\/jphysiol.1991.sp018523","article-title":"Characteristics of fluid secretion from isolated rat pancreatic ducts stimulated with secretin and bombesin","volume":"435","author":"Ashton","year":"1991","journal-title":"J Physiol (Lond)"},{"key":"2023072918182590700_B3","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1146\/annurev.ph.52.030190.000525","article-title":"The serous cell","volume":"52","author":"Basbaum","year":"1990","journal-title":"Annu Rev Physiol"},{"key":"2023072918182590700_B4"},{"key":"2023072918182590700_B5","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1085\/jgp.81.1.53","article-title":"Intracellular pH regulation in the renal proximal tubule of the salamander","volume":"81","author":"Boron","year":"1983","journal-title":"J Gen Physiol"},{"key":"2023072918182590700_B6","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/ki.1989.208","article-title":"The electrogenic Na\/HCO3 cotransporter","volume":"36","author":"Boron","year":"1989","journal-title":"Kidney Int"},{"key":"2023072918182590700_B7","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1085\/jgp.93.1.123","article-title":"Intracellular pH-regulating mechanism of the squid axon. 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