{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:17:50Z","timestamp":1790054270160,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:00:00Z","timestamp":1645056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Regardless of its aetiology, sustained intracellular Ca<jats:sup>2+<\/jats:sup> overload is a well\u2010known hallmark of acute pancreatitis (AP). Toxic Ca<jats:sup>2+<\/jats:sup> elevation induces pancreatic ductal cell damage characterized by impaired ion and fluid secretion \u2013 essential to wash out the protein\u2010rich fluid secreted by acinar cells while maintaining the alkaline intra\u2010ductal pH under physiological conditions \u2013 and mitochondrial dysfunction. While prevention of ductal cell injury decreases the severity of AP, no specific drug target has yet been identified in the ductal cells. Although Orai1, a store\u2010operated Ca<jats:sup>2+<\/jats:sup> influx channel, is known to contribute to sustained Ca<jats:sup>2+<\/jats:sup> overload in acinar cells, details concerning its expression and function in ductal cells are currently lacking. In this study, we demonstrate that functionally active Orai1 channels reside predominantly in the apical plasma membrane of pancreatic ductal cells. Selective CM5480\u2010mediated Orai1 inhibition impairs Stim1\u2010dependent extracellular Ca<jats:sup>2+<\/jats:sup> influx evoked by bile acids or ethanol combined with non\u2010oxidative ethanol metabolites. Furthermore, prevention of sustained extracellular Ca<jats:sup>2+<\/jats:sup> influx protects ductal cell secretory function <jats:italic>in vitro<\/jats:italic> and decreases pancreatic ductal cell death. Finally, Orai1 inhibition partially restores and maintains proper exocrine pancreatic secretion in <jats:italic>in vivo<\/jats:italic> AP models. In conclusion, our results indicate that Orai1 inhibition prevents AP\u2010related ductal cell function impairment and holds the potential of improving disease outcome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Sustained intracellular Ca<jats:sup>2+<\/jats:sup> overload in pancreatic acinar and ductal cells is a hallmark of biliary and alcohol\u2010induced acute pancreatitis, which leads to impaired ductal ion and fluid secretion.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Orai1 is a plasma membrane Ca<jats:sup>2+<\/jats:sup> channel that mediates extracellular Ca<jats:sup>2+<\/jats:sup> influx upon endoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> depletion.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Results showed that Orai1 is expressed on the luminal plasma membrane of the ductal cells and selective Orai1 inhibition impaired Stim1\u2010dependent extracellular Ca<jats:sup>2+<\/jats:sup> influx evoked by bile acids or ethanol combined with non\u2010oxidative ethanol metabolites.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The prevention of sustained extracellular Ca<jats:sup>2+<\/jats:sup> influx protected ductal cell secretory functions in <jats:italic>in vitro<\/jats:italic> models and maintained exocrine pancreatic secretion in <jats:italic>in vivo<\/jats:italic> acute pancreatitis models.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Orai1 inhibition prevents the bile acid\u2010 and alcohol\u2010induced damage of the pancreatic ductal secretion and holds the potential of improving the outcome of acute pancreatitis.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282203","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:41:18Z","timestamp":1643244078000},"page":"1631-1650","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Bile acid\u2010 and ethanol\u2010mediated activation of Orai1 damages pancreatic ductal secretion in acute pancreatitis"],"prefix":"10.1113","volume":"600","author":[{"given":"Petra","family":"Pallagi","sequence":"first","affiliation":[{"name":"HCEMM\u2010SZTE Molecular Gastroenterology Research Group University of Szeged  Szeged Hungary"},{"name":"Department of Medicine University of Szeged  Szeged Hungary"},{"name":"ELKH\u2010USZ Momentum Epithelial Cell Signaling and Secretion Research Group University of Szeged  Szeged 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