Mechanosensitive Cl- secretion in biliary epithelium mediated through TMEM16A

Amal K. Dutta, Kangmee Woo, Al karim Khimji, Charles Kresge, Andrew P. Feranchak

Research output: Contribution to journalArticle

23 Scopus citations

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 Ca2+-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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)G87-G98
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume304
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • ATP release
  • Anoctamin-1
  • Chloride channel
  • Cholangiocyte
  • Liver
  • Purinergic signaling

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Mechanosensitive Cl<sup>-</sup> secretion in biliary epithelium mediated through TMEM16A'. Together they form a unique fingerprint.

  • Cite this