Bile acids stimulate cholangiocyte fluid secretion by activation of transmembrane member 16A Cl- channels

Qin Li, Amal Dutta, Charles Kresge, Abhijit Bugde, Andrew P. Feranchak

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Bile acids stimulate a bicarbonate-rich choleresis, in part, through effects on cholangiocytes. Because Cl- channels in the apical membrane of cholangiocytes provide the driving force for secretion and transmembrane member 16A (TMEM16A) has been identified as the Ca2+-activated Cl- channel in the apical membrane of cholangiocytes, the aim of the present study was to determine whether 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 pharmacological or molecular (small-interfering RNA; 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.

Original languageEnglish (US)
JournalHepatology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Fluids and Secretions
Bile Acids and Salts
Membranes
Adenosine Triphosphate
Small Interfering RNA
Apyrase
Inositol 1,4,5-Trisphosphate Receptors
Suramin
Ursodeoxycholic Acid
Inositol 1,4,5-Trisphosphate
Cholestasis
Exocytosis
Bicarbonates
Bile
Permeability
Epithelium
Pharmacology
tauroursodeoxycholic acid

ASJC Scopus subject areas

  • Hepatology

Cite this

Bile acids stimulate cholangiocyte fluid secretion by activation of transmembrane member 16A Cl- channels. / Li, Qin; Dutta, Amal; Kresge, Charles; Bugde, Abhijit; Feranchak, Andrew P.

In: Hepatology, 01.01.2018.

Research output: Contribution to journalArticle

@article{70f63784084a4b6b9cb3ac7e20ab71a9,
title = "Bile acids stimulate cholangiocyte fluid secretion by activation of transmembrane member 16A Cl- channels",
abstract = "Bile acids stimulate a bicarbonate-rich choleresis, in part, through effects on cholangiocytes. Because Cl- channels in the apical membrane of cholangiocytes provide the driving force for secretion and transmembrane member 16A (TMEM16A) has been identified as the Ca2+-activated Cl- channel in the apical membrane of cholangiocytes, the aim of the present study was to determine whether 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 pharmacological or molecular (small-interfering RNA; 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.",
author = "Qin Li and Amal Dutta and Charles Kresge and Abhijit Bugde and Feranchak, {Andrew P.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1002/hep.29804",
language = "English (US)",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",

}

TY - JOUR

T1 - Bile acids stimulate cholangiocyte fluid secretion by activation of transmembrane member 16A Cl- channels

AU - Li, Qin

AU - Dutta, Amal

AU - Kresge, Charles

AU - Bugde, Abhijit

AU - Feranchak, Andrew P.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Bile acids stimulate a bicarbonate-rich choleresis, in part, through effects on cholangiocytes. Because Cl- channels in the apical membrane of cholangiocytes provide the driving force for secretion and transmembrane member 16A (TMEM16A) has been identified as the Ca2+-activated Cl- channel in the apical membrane of cholangiocytes, the aim of the present study was to determine whether 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 pharmacological or molecular (small-interfering RNA; 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.

AB - Bile acids stimulate a bicarbonate-rich choleresis, in part, through effects on cholangiocytes. Because Cl- channels in the apical membrane of cholangiocytes provide the driving force for secretion and transmembrane member 16A (TMEM16A) has been identified as the Ca2+-activated Cl- channel in the apical membrane of cholangiocytes, the aim of the present study was to determine whether 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 pharmacological or molecular (small-interfering RNA; 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.

UR - http://www.scopus.com/inward/record.url?scp=85046689999&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046689999&partnerID=8YFLogxK

U2 - 10.1002/hep.29804

DO - 10.1002/hep.29804

M3 - Article

JO - Hepatology

JF - Hepatology

SN - 0270-9139

ER -