The lipid products of phosphoinositide 3-kinase contribute to regulation of cholangiocyte ATP and chloride transport.
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.
Feranchak
A P
AP
Department of Pediatrics, Children's Hospital, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. drew.feranchak@UCHSC.edu
Roman
R M
RM
Doctor
R B
RB
Salter
K D
KD
Toker
A
A
Fitz
J G
JG
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001650:Bile Duct Neoplasms; D001652:Bile Ducts / Q000166:cytology / Q000502:physiology*; D001653:Bile Ducts, Intrahepatic; D001692:Biological Transport; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D018281:Cholangiocarcinoma; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007038:Hypotonic Solutions; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D002712:Chlorides; D002867:Chromones; D004791:Enzyme Inhibitors; D007038:Hypotonic Solutions; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D000077191:Wortmannin