title: Regulation of mechanosensitive biliary epithelial transport by the epithelial Na(+) channel.
abstract: Intrahepatic biliary epithelial cells (BECs), also known as cholangiocytes, modulate the volume and composition of bile through the regulation of secretion and absorption. While mechanosensitive Cl(-) efflux has been identified as an important secretory pathway, the counterabsorptive pathways have not been identified. In other epithelial cells, the epithelial Na(+) channel (ENaC) has been identified as an important contributor to fluid absorption; however, its expression and function in BECs have not been previously studied. Our studies revealed the presence of α, β, and γ ENaC subunits in human BECs and α and γ subunits in mouse BECs. In studies of confluent mouse BEC monolayers, the ENaC contributes to the volume of surface fluid at the apical membrane during constitutive conditions. Further, functional studies using whole-cell patch clamp of single BECs demonstrated small constitutive Na(+) currents, which increased significantly in response to fluid-flow or shear. The magnitude of Na(+) currents was proportional to the shear force, displayed inward rectification and a reversal potential of +40 mV (ENa+  = +60 mV), and were abolished with removal of extracellular Na(+) (N-methyl-d-glucamine) or in the presence of amiloride. Transfection with ENaCα small interfering RNA significantly inhibited flow-stimulated Na(+) currents, while overexpression of the α subunit significantly increased currents. ENaC-mediated currents were positively regulated by proteases and negatively regulated by extracellular adenosine triphosphate.
  
  
  CONCLUSIONS
  These studies represent the initial characterization of mechanosensitive Na(+) currents activated by flow in biliary epithelium; understanding the role of mechanosensitive transport pathways may provide strategies to modulate the volume and composition of bile during cholestatic conditions. (Hepatology 2016;63:538-549).
authors.affiliation: Department of Physiology, Jianhan University School of Medicine, Wuhan, China.|Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Charles
authors.initials: C
authors.lastname: Kresge
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Bugde
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Health, Children's Medical Center, Dallas, TX.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lamphere
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Health, Children's Medical Center, Dallas, TX.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.|Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Jason Y
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feranchak
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000502:physiology*; D001692:Biological Transport / Q000502:physiology*; D002478:Cells, Cultured; D053503:Epithelial Sodium Channels / Q000502:physiology*; D004848:Epithelium / Q000502:physiology*; D006801:Humans; D008465:Mechanoreceptors / Q000502:physiology*; D051379:Mice
chemical_list: D053503:Epithelial Sodium Channels