{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:18:18Z","timestamp":1791321498846,"version":"4.3.1"},"reference-count":56,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2015,12,7]],"date-time":"2015-12-07T00:00:00Z","timestamp":1449446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2015,12,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Fluid and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> secretion is essential for all epithelia; aberrant secretion is associated with several diseases.\n<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Carbonic anhydrase XII (CA12) is the key carbonic anhydrase in epithelial fluid and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> secretion and works by activating the ductal Cl<jats:sup>\u2212<\/jats:sup>\u2013HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> exchanger AE2.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Delivery of CA12 to salivary glands increases salivation in mice and of the human mutation CA12(E143K) markedly inhibits it.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The human mutation CA12(E143K) causes disease due to aberrant CA12 glycosylation, and misfolding resulting in loss of AE2 activity.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Aberrant epithelial fluid and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> secretion is associated with many diseases. The activity of HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> transporters depends of HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> availability that is determined by carbonic anhydrases (CAs). Which CAs are essential for epithelial function is unknown. CA12 stands out since the CA12(E143K) mutation causes salt wasting in sweat and dehydration in humans. Here, we report that expression of CA12 and of CA12(E143K) in mice salivary glands respectively increased and prominently inhibited ductal fluid secretion and salivation <jats:italic>in vivo<\/jats:italic>. CA12 markedly increases the activity and is the major HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> supplier of ductal Cl<jats:sup>\u2212<\/jats:sup>\u2013HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> exchanger AE2, but not of NBCe1\u2010B. The E143K mutation alters CA12 glycosylation at N28 and N80, resulting in retention of the basolateral CA12 in the ER. Knockdown of AE2 and of CA12 inhibited pancreatic and salivary gland ductal AE2 activity and fluid secretion. Accordingly, patients homozygous for the CA12(E143K) mutation have a dry mouth, dry tongue phenotype. These findings reveal an unsuspected prominent role of CA12 in epithelial function, explain the disease and call for caution in the use of CA12 inhibitors in cancer treatment.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp271378","type":"journal-article","created":{"date-parts":[[2015,10,21]],"date-time":"2015-10-21T10:08:52Z","timestamp":1445422132000},"page":"5299-5312","source":"Crossref","is-referenced-by-count":44,"title":["Essential role of carbonic anhydrase XII in secretory gland fluid and HCO<sub>3<\/sub><sup>\u2212<\/sup> secretion revealed by disease causing human mutation"],"prefix":"10.1113","volume":"593","author":[{"given":"Jeong Hee","family":"Hong","sequence":"first","affiliation":[{"name":"Epithelial Signalling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research National Institutes of Health  Bethesda MD 20892 USA"},{"name":"Department of Physiology, College of Medicine Gachon University  191 Hambakmeoro Yeonsu\u2010gu Incheon 406\u2010799 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emad","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Shraga Segal Department of Microbiology, Immunology and Genetics Faculty of Health Sciences and National Institute for Biotechnology in the Negev  Beer Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyu","family":"Zheng","sequence":"additional","affiliation":[{"name":"Epithelial Signalling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research National Institutes of Health  Bethesda MD 20892 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Hershkovitz","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Unit, Soroka Medical Centre and Faculty of Health Sciences Ben Gurion University of the Negev  Beer Sheva 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