{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:14:32Z","timestamp":1791051272696,"version":"4.1.0"},"reference-count":46,"publisher":"American Society for Cell Biology (ASCB)","issue":"15","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2010,8]]},"abstract":"<jats:p>Chloride secretion by airway epithelial cells is defective in cystic fibrosis (CF). The conventional paradigm is that CFTR is activated through cAMP and protein kinase A (PKA), whereas the Ca<jats:sup>2+<\/jats:sup>-activated chloride channel (CaCC) is activated by Ca<jats:sup>2+<\/jats:sup>agonists like UTP. We found that most chloride current elicited by Ca<jats:sup>2+<\/jats:sup>agonists in primary cultures of human bronchial epithelial cells is mediated by CFTR by a mechanism involving Ca<jats:sup>2+<\/jats:sup>activation of adenylyl cyclase I (AC1) and cAMP\/PKA signaling. Use of selective inhibitors showed that Ca<jats:sup>2+<\/jats:sup>agonists produced more chloride secretion from CFTR than from CaCC. CFTR-dependent chloride secretion was reduced by PKA inhibition and was absent in CF cell cultures. Ca<jats:sup>2+<\/jats:sup>agonists produced cAMP elevation, which was blocked by adenylyl cyclase inhibition. AC1, a Ca<jats:sup>2+<\/jats:sup>\/calmodulin-stimulated adenylyl cyclase, colocalized with CFTR in the cell apical membrane. RNAi knockdown of AC1 selectively reduced UTP-induced cAMP elevation and chloride secretion. These results, together with correlations between cAMP and chloride current, suggest that compartmentalized AC1\u2013CFTR association is responsible for Ca<jats:sup>2+<\/jats:sup>\/cAMP cross-talk. We further conclude that CFTR is the principal chloride secretory pathway in non-CF airways for both cAMP and Ca<jats:sup>2+<\/jats:sup>agonists, providing a novel mechanism to link CFTR dysfunction to CF lung disease.<\/jats:p>","DOI":"10.1091\/mbc.e09-12-1004","type":"journal-article","created":{"date-parts":[[2010,6,17]],"date-time":"2010-06-17T01:54:43Z","timestamp":1276739683000},"page":"2639-2648","source":"Crossref","is-referenced-by-count":70,"title":["CFTR-Adenylyl Cyclase I Association Responsible for UTP Activation of CFTR in Well-Differentiated Primary Human Bronchial Cell Cultures"],"prefix":"10.1091","volume":"21","author":[{"given":"Wan","family":"Namkung","sequence":"first","affiliation":[{"name":"Departments of *Medicine and Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter E.","family":"Finkbeiner","sequence":"additional","affiliation":[{"name":"Pathology, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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