Bile acids stimulate cholangiocyte fluid secretion by activation of membraneTMEM16A Cl- channels

Abstract

Bile acids stimulate a bicarbonate-rich choleresis in part through effects on cholangiocytes. As Cl^- channels in the apical membrane of cholangiocytes provide the driving force for secretion and TMEM16A has been identified as the Ca²⁺-activated Cl^- channel in the apical membrane of cholangiocytes (1), the aim of the present study was to determine if TMEM16A is the target of bile acid-stimulated Cl^- secretion and to identify the regulatory pathway involved. In these studies of mouse, rat, and human biliary epithelium exposure to Ursodeoxycholic acid (UDCA) or Tauroursodeoxycholic acid (TUDCA) rapidly increased the rate of exocytosis, ATP release, [Ca²⁺]_i, membrane Cl^- permeability, and transepithelial secretion. Bile acid-stimulated Cl^- currents demonstrated biophysical properties consistent with TMEM16A and were inhibited by pharmacologic or molecular (siRNA) inhibition of TMEM16A. Bile acid-stimulated Cl^- currents were not observed in the presence of apyrase, suramin, or 2-aminoethoxydiphenyl borate (2-APB), demonstrating that current activation requires extracellular ATP, P2Y, and inositol 1,4,5-trisphosphate (IP3) receptors. TUDCA did not activate Cl^- currents during pharmacologic inhibition of the apical Na⁺-dependent bile acid transporter (ASBT), but direct intracellular delivery of TUDCA rapidly activated Cl^- currents. Conclusion: Bile acids stimulate Cl^- secretion in mouse and human biliary cells through activation of membrane TMEM16A channels in a process regulated by extracellular ATP and [Ca²⁺]_i. These studies suggest that TMEM16A channels may be targets to increase bile flow during cholestasis. This article is protected by copyright. All rights reserved.

http://ift.tt/2n5M88X