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.
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U2 - 10.1074/jbc.274.43.30979
DO - 10.1074/jbc.274.43.30979
M3 - Article
C2 - 10521494
AN - SCOPUS:0032725310
SN - 0021-9258
VL - 274
SP - 30979
EP - 30986
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -