title: Mechanosensitive Cl- secretion in biliary epithelium mediated through TMEM16A.
abstract: Bile formation by the liver is initiated by canalicular transport at the hepatocyte membrane, leading to an increase in ductular bile flow. Thus, bile duct epithelial cells (cholangiocytes), which contribute to the volume and dilution of bile through regulated Cl(-) transport, are exposed to changes in flow and shear force at the apical membrane. The aim of the present study was to determine if fluid flow, or shear stress, is a signal regulating cholangiocyte transport. The results demonstrate that, in human and mouse biliary cells, fluid flow, or shear, increases Cl(-) currents and identify TMEM16A, a Ca(2+)-activated Cl(-) channel, as the operative channel. Furthermore, activation of TMEM16A by flow is dependent on PKCα through a process involving extracellular ATP, binding purinergic P2 receptors, and increases in intracellular Ca(2+) concentration. These studies represent the initial characterization of mechanosensitive Cl(-) currents mediated by TMEM16A. Identification of this novel mechanosensitive secretory pathway provides new insight into bile formation and suggests new therapeutic targets to enhance bile formation in the treatment of cholestatic liver disorders.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9063, USA. amal.dutta@utsouthwestern.edu
authors.forename: Amal K
authors.initials: AK
authors.lastname: Dutta
authors.forename: Kangmee
authors.initials: K
authors.lastname: Woo
authors.forename: Al-karim
authors.initials: AK
authors.lastname: Khimji
authors.forename: Charles
authors.initials: C
authors.lastname: Kresge
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feranchak
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000075369:Anoctamin-1; D001659:Biliary Tract / Q000166:cytology / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology; D004848:Epithelium / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010477:Perfusion; D051571:Protein Kinase C-alpha / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism; D014783:Viscosity
chemical_list: C476213:ANO1 protein, human; C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D002712:Chlorides; D009363:Neoplasm Proteins; D018048:Receptors, Purinergic P2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate; D051571:Protein Kinase C-alpha