The lipid products of phosphoinositide 3-kinase contribute to regulation of cholangiocyte ATP and chloride transport

Andrew P. Feranchak, Richard M. Roman, R. Brian Doctor, Kelli D. Salter, Alex Toker, J. Gregory Fitz

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

ATP stimulates Cl- secretion and bile formation by activation of purinergic receptors in the apical membrane of cholangiocytes. The purpose of these studies was to determine the cellular origin of biliary ATP and to assess the regulatory pathways involved in its release. In Mz-Cha-1 human cholangiocarcinoma cells, increases in cell volume were followed by increases in phophoinositide (PI) 3-kinase activity, ATP release, and membrane Cl- permeability. PI 3-kinase signaling appears to play a regulatory role because ATP release was inhibited by wortmannin or LY294002 and because volume- sensitive current activation was inhibited by intracellular dialysis with antibodies to the 110 kDa-subunit of PI 3-kinase. Similarly, in intact normal rat cholangiocyte monolayers, increases in cell volume stimulated luminal Cl- secretion through a wortmannin-sensitive pathway. To assess the role of PI 3-kinase more directly, cells were dialyzed with the synthetic lipid products of PI 3-kinase. Intracellular delivery of phosphatidylinositol 3,4- bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate activated Cl- currents analogous to those observed following cell swelling. Taken together, these findings indicate that volume-sensitive activation of PI 3-kinase and the generation of lipid messengers modulate cholangiocyte ATP release, Cl- secretion, and, hence, bile formation.

Original languageEnglish (US)
Pages (from-to)30979-30986
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number43
DOIs
StatePublished - Oct 22 1999

Fingerprint

1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Chlorides
Phosphotransferases
Adenosine Triphosphate
Lipids
Chemical activation
Cell Size
Bile
Membranes
Purinergic Receptors
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Dialysis
Cholangiocarcinoma
Swelling
Rats
Monolayers
Permeability
Antibodies

ASJC Scopus subject areas

  • Biochemistry

Cite this

The lipid products of phosphoinositide 3-kinase contribute to regulation of cholangiocyte ATP and chloride transport. / Feranchak, Andrew P.; Roman, Richard M.; Doctor, R. Brian; Salter, Kelli D.; Toker, Alex; Fitz, J. Gregory.

In: Journal of Biological Chemistry, Vol. 274, No. 43, 22.10.1999, p. 30979-30986.

Research output: Contribution to journalArticle

Feranchak, Andrew P. ; Roman, Richard M. ; Doctor, R. Brian ; Salter, Kelli D. ; Toker, Alex ; Fitz, J. Gregory. / The lipid products of phosphoinositide 3-kinase contribute to regulation of cholangiocyte ATP and chloride transport. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 43. pp. 30979-30986.
@article{65c5883b89914b86abed10d269415944,
title = "The lipid products of phosphoinositide 3-kinase contribute to regulation of cholangiocyte ATP and chloride transport",
abstract = "ATP stimulates Cl- secretion and bile formation by activation of purinergic receptors in the apical membrane of cholangiocytes. The purpose of these studies was to determine the cellular origin of biliary ATP and to assess the regulatory pathways involved in its release. In Mz-Cha-1 human cholangiocarcinoma cells, increases in cell volume were followed by increases in phophoinositide (PI) 3-kinase activity, ATP release, and membrane Cl- permeability. PI 3-kinase signaling appears to play a regulatory role because ATP release was inhibited by wortmannin or LY294002 and because volume- sensitive current activation was inhibited by intracellular dialysis with antibodies to the 110 kDa-subunit of PI 3-kinase. Similarly, in intact normal rat cholangiocyte monolayers, increases in cell volume stimulated luminal Cl- secretion through a wortmannin-sensitive pathway. To assess the role of PI 3-kinase more directly, cells were dialyzed with the synthetic lipid products of PI 3-kinase. Intracellular delivery of phosphatidylinositol 3,4- bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate activated Cl- currents analogous to those observed following cell swelling. Taken together, these findings indicate that volume-sensitive activation of PI 3-kinase and the generation of lipid messengers modulate cholangiocyte ATP release, Cl- secretion, and, hence, bile formation.",
author = "Feranchak, {Andrew P.} and Roman, {Richard M.} and Doctor, {R. Brian} and Salter, {Kelli D.} and Alex Toker and Fitz, {J. Gregory}",
year = "1999",
month = "10",
day = "22",
doi = "10.1074/jbc.274.43.30979",
language = "English (US)",
volume = "274",
pages = "30979--30986",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "43",

}

TY - JOUR

T1 - The lipid products of phosphoinositide 3-kinase contribute to regulation of cholangiocyte ATP and chloride transport

AU - Feranchak, Andrew P.

AU - Roman, Richard M.

AU - Doctor, R. Brian

AU - Salter, Kelli D.

AU - Toker, Alex

AU - Fitz, J. Gregory

PY - 1999/10/22

Y1 - 1999/10/22

N2 - ATP stimulates Cl- secretion and bile formation by activation of purinergic receptors in the apical membrane of cholangiocytes. The purpose of these studies was to determine the cellular origin of biliary ATP and to assess the regulatory pathways involved in its release. In Mz-Cha-1 human cholangiocarcinoma cells, increases in cell volume were followed by increases in phophoinositide (PI) 3-kinase activity, ATP release, and membrane Cl- permeability. PI 3-kinase signaling appears to play a regulatory role because ATP release was inhibited by wortmannin or LY294002 and because volume- sensitive current activation was inhibited by intracellular dialysis with antibodies to the 110 kDa-subunit of PI 3-kinase. Similarly, in intact normal rat cholangiocyte monolayers, increases in cell volume stimulated luminal Cl- secretion through a wortmannin-sensitive pathway. To assess the role of PI 3-kinase more directly, cells were dialyzed with the synthetic lipid products of PI 3-kinase. Intracellular delivery of phosphatidylinositol 3,4- bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate activated Cl- currents analogous to those observed following cell swelling. Taken together, these findings indicate that volume-sensitive activation of PI 3-kinase and the generation of lipid messengers modulate cholangiocyte ATP release, Cl- secretion, and, hence, bile formation.

AB - ATP stimulates Cl- secretion and bile formation by activation of purinergic receptors in the apical membrane of cholangiocytes. The purpose of these studies was to determine the cellular origin of biliary ATP and to assess the regulatory pathways involved in its release. In Mz-Cha-1 human cholangiocarcinoma cells, increases in cell volume were followed by increases in phophoinositide (PI) 3-kinase activity, ATP release, and membrane Cl- permeability. PI 3-kinase signaling appears to play a regulatory role because ATP release was inhibited by wortmannin or LY294002 and because volume- sensitive current activation was inhibited by intracellular dialysis with antibodies to the 110 kDa-subunit of PI 3-kinase. Similarly, in intact normal rat cholangiocyte monolayers, increases in cell volume stimulated luminal Cl- secretion through a wortmannin-sensitive pathway. To assess the role of PI 3-kinase more directly, cells were dialyzed with the synthetic lipid products of PI 3-kinase. Intracellular delivery of phosphatidylinositol 3,4- bisphosphate, and phosphatidylinositol 3,4,5-trisphosphate activated Cl- currents analogous to those observed following cell swelling. Taken together, these findings indicate that volume-sensitive activation of PI 3-kinase and the generation of lipid messengers modulate cholangiocyte ATP release, Cl- secretion, and, hence, bile formation.

UR - http://www.scopus.com/inward/record.url?scp=0032725310&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032725310&partnerID=8YFLogxK

U2 - 10.1074/jbc.274.43.30979

DO - 10.1074/jbc.274.43.30979

M3 - Article

C2 - 10521494

AN - SCOPUS:0032725310

VL - 274

SP - 30979

EP - 30986

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 43

ER -