{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T14:40:50Z","timestamp":1791038450185,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":792,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>Large, but not small, cholangiocytes (1) secrete bicarbonate by interaction with secretin receptors (SRs) through activation of cystic fibrosis transmembrane regulator (CFTR), Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub>\n                                 <jats:sup>\u2212<\/jats:sup> (apex) anion exchanger 2 (Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub>\n                                 <jats:sup>\u2212<\/jats:sup> AE2), and adenylyl cyclase (AC)8 (proteins regulating large biliary functions) and (2) proliferate in response to bile duct ligation (BDL) by activation of cyclic adenosine monophosphate (cAMP) signaling. Small, mitotically dormant cholangiocytes are activated during damage of large cholangiocytes by activation of D-<jats:italic toggle=\"yes\">myo<\/jats:italic>-inositol 1,4,5-trisphosphate\/Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent protein kinase (CaMK) I. gamma-Aminobutyric acid (GABA) affects cell functions by modulation of Ca<jats:sup>2+<\/jats:sup>-dependent signaling and AC. We hypothesized that GABA induces the differentiation of small into large cholangiocytes by the activation of Ca<jats:sup>2+<\/jats:sup>\/CaMK I-dependent AC8. <jats:italic toggle=\"yes\">In vivo<\/jats:italic>, BDL mice were treated with GABA in the absence or presence of 1,2-bis-(o-aminophenoxy)-ethane-N,N,N\u2032,N\u2032-tetraacetic acid, tetraacetoxymethyl ester (BAPTA\/AM) or N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide (W7) before evaluating apoptosis and intrahepatic bile ductal mass (IBDM) of small and large cholangiocytes. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, control- or CaMK I-silenced small cholangiocytes were treated with GABA for 3 days before evaluating apoptosis, proliferation, ultrastructural features, and the expression of CFTR, Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub>\n                                 <jats:sup>\u2212<\/jats:sup> AE2, AC8, and secretin-stimulated cAMP levels. <jats:italic toggle=\"yes\">In vivo<\/jats:italic> administration of GABA induces the apoptosis of large, but not small, cholangiocytes and decreases large IBDM, but increased <jats:italic toggle=\"yes\">de novo<\/jats:italic> small IBDM. GABA stimulation of small IBDM was blocked by BAPTA\/AM and W7. Subsequent to GABA <jats:italic toggle=\"yes\">in vitro<\/jats:italic> treatment, small cholangiocytes <jats:italic toggle=\"yes\">de novo<\/jats:italic> proliferate and acquire ultrastructural and functional phenotypes of large cholangiocytes and respond to secretin. GABA-induced changes were prevented by BAPTA\/AM, W7, and stable knockdown of the CaMK I gene. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: GABA damages large, but not small, cholangiocytes that differentiate into large cholangiocytes. The differentiation of small into large cholangiocytes may be important in the replenishment of the biliary epithelium during damage of large, senescent cholangiocytes. (HEPATOLOGY 2013;)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26308","type":"journal-article","created":{"date-parts":[[2013,2,7]],"date-time":"2013-02-07T00:26:55Z","timestamp":1360196815000},"page":"251-263","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":39,"title":["GABA induces the differentiation of small into large cholangiocytes by activation of Ca2+\/CaMK I-dependent adenylyl cyclase 8"],"prefix":"10.1097","volume":"58","author":[{"given":"Romina","family":"Mancinelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Franchitto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Glaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanyin","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Onori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"DeMorrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Venter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Carpino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberley","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Gaudio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Alpini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-29-20241201","doi-asserted-by":"crossref","first-page":"G1064G1074","DOI":"10.1152\/ajpgi.1997.272.5.G1064","article-title":"Large but not small intrahepatic bile ducts are involved in secretinregulated ductal bile secretion.","volume":"272","author":"Alpini","year":"1997","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R2-29-20241201","doi-asserted-by":"crossref","first-page":"G289G297","DOI":"10.1152\/ajpgi.1997.272.2.G289","article-title":"Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation.","volume":"272","author":"Alpini","year":"1997","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R3-29-20241201","doi-asserted-by":"crossref","first-page":"456469","DOI":"10.1038\/labinvest.2009.6","article-title":"Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium.","volume":"89","author":"Glaser","year":"2009","journal-title":"Lab Invest"},{"key":"R4-29-20241201","doi-asserted-by":"crossref","first-page":"C499C513","DOI":"10.1152\/ajpcell.00369.2007","article-title":"Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3CaMK ICREB pathway.","volume":"295","author":"Francis","year":"2008","journal-title":"Am J Physiol Cell Physiol"},{"key":"R5-29-20241201","doi-asserted-by":"crossref","first-page":"G767G775","DOI":"10.1152\/ajpgi.1998.274.4.G767","article-title":"Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation.","volume":"274","author":"Alpini","year":"1998","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R6-29-20241201","doi-asserted-by":"crossref","first-page":"555561","DOI":"10.1002\/hep.510310302","article-title":"Functional heterogeneity of the intrahepatic biliary epithelium.","volume":"31","author":"Kanno","year":"2000","journal-title":"HEPATOLOGY"},{"key":"R7-29-20241201","doi-asserted-by":"crossref","first-page":"16361643","DOI":"10.1053\/gast.1996.v110.pm8613073","article-title":"Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver.","volume":"110","author":"Alpini","year":"1996","journal-title":"Gastroenterology"},{"key":"R8-29-20241201","doi-asserted-by":"crossref","first-page":"569578","DOI":"10.1172\/JCI113355","article-title":"Biliary physiology in rats with bile ductular cell hyperplasia. 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