{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T15:04:39Z","timestamp":1787929479564,"version":"build-2784847793"},"reference-count":47,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2009,1]]},"abstract":"<jats:p>Cystic fibrosis (CF) is caused by mutations in the gene producing the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a Cl<jats:sup>\u2212<\/jats:sup>channel. Its dysfunction limits Cl<jats:sup>\u2212<\/jats:sup>secretion and enhances Na<jats:sup>+<\/jats:sup>absorption, leading to viscous mucus in the airway. Ca<jats:sup>2+<\/jats:sup>-activated Cl<jats:sup>\u2212<\/jats:sup>channels (CaCCs) are coexpressed with CFTR in the airway surface epithelia. Increases in cytosolic Ca<jats:sup>2+<\/jats:sup>activate the epithelial CaCCs, which provides an alternative Cl<jats:sup>\u2212<\/jats:sup>secretory pathway in CF. We developed a screening assay and screened a library for compounds that could enhance cytoplasmic Ca<jats:sup>2+<\/jats:sup>, activate the CaCC, and increase Cl<jats:sup>\u2212<\/jats:sup>secretion. We found that spiperone, a known antipsychotic drug, is a potent intracellular Ca<jats:sup>2+<\/jats:sup>enhancer and demonstrated that it stimulates intracellular Ca<jats:sup>2+<\/jats:sup>, not by acting in its well-known role as an antagonist of serotonin 5-HT<jats:sub>2<\/jats:sub>or dopamine D<jats:sub>2<\/jats:sub>receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Spiperone activates CaCCs, which stimulates Cl<jats:sup>\u2212<\/jats:sup>secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro and in CFTR-knockout mice in vivo. In conclusion, we have identified spiperone as a new therapeutic platform for correction of defective Cl<jats:sup>\u2212<\/jats:sup>secretion in CF via a pathway independent of CFTR.<\/jats:p>","DOI":"10.1152\/ajpcell.00346.2008","type":"journal-article","created":{"date-parts":[[2008,11,6]],"date-time":"2008-11-06T01:54:56Z","timestamp":1225936496000},"page":"C131-C141","source":"Crossref","is-referenced-by-count":13,"title":["Spiperone, identified through compound screening, activates calcium-dependent chloride secretion in the airway"],"prefix":"10.1152","volume":"296","author":[{"given":"Lihua","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik M.","family":"Schwiebert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela 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