Identification and Functional Characterization of TMEM16A, a Ca2+-activated Cl− Channel Activated by Extracellular Nucleotides, in Biliary Epithelium

Cl− channels in the apical membrane of biliary epithelial cells (BECs) provide the driving force for ductular bile formation. Although a cystic fibrosis transmembrane conductance regulator has been identified in BECs and contributes to secretion via secretin binding basolateral receptors and increas...

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Veröffentlicht in:The Journal of biological chemistry 2011-01, Vol.286 (1), p.766-776
Hauptverfasser: Dutta, Amal K., Khimji, Al-karim, Kresge, Charles, Bugde, Abhijit, Dougherty, Michael, Esser, Victoria, Ueno, Yoshiyuki, Glaser, Shannon S., Alpini, Gianfranco, Rockey, Don C., Feranchak, Andrew P.
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Sprache:eng
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Zusammenfassung:Cl− channels in the apical membrane of biliary epithelial cells (BECs) provide the driving force for ductular bile formation. Although a cystic fibrosis transmembrane conductance regulator has been identified in BECs and contributes to secretion via secretin binding basolateral receptors and increasing [cAMP]i, an alternate Cl− secretory pathway has been identified that is activated via nucleotides (ATP, UTP) binding apical P2 receptors and increasing [Ca2+]i. The molecular identity of this Ca2+-activated Cl− channel is unknown. The present studies in human, mouse, and rat BECs provide evidence that TMEM16A is the operative channel and contributes to Ca2+-activated Cl− secretion in response to extracellular nucleotides. Furthermore, Cl− currents measured from BECs isolated from distinct areas of intrahepatic bile ducts revealed important functional differences. Large BECs, but not small BECs, exhibit cAMP-stimulated Cl− currents. However, both large and small BECs express TMEM16A and exhibit Ca2+-activated Cl− efflux in response to extracellular nucleotides. Incubation of polarized BEC monolayers with IL-4 increased TMEM16A protein expression, membrane localization, and transepithelial secretion (Isc). These studies represent the first molecular identification of an alternate, noncystic fibrosis transmembrane conductance regulator, Cl− channel in BECs and suggest that TMEM16A may be a potential target to modulate bile formation in the treatment of cholestatic liver disorders.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.164970