title: Phosphatidylinositol 3-kinase facilitates bile acid-induced Ca(2+) responses in pancreatic acinar cells.
abstract: Bile acids are known to induce Ca(2+) signals in pancreatic acinar cells. We have recently shown that phosphatidylinositol 3-kinase (PI3K) regulates changes in free cytosolic Ca(2+) concentration ([Ca(2+)](i)) elicited by CCK by inhibiting sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). The present study sought to determine whether PI3K regulates bile acid-induced [Ca(2+)](i) responses. In pancreatic acinar cells, pharmacological inhibition of PI3K with LY-294002 or wortmannin inhibited [Ca(2+)](i) responses to taurolithocholic acid 3-sulfate (TLC-S) and taurochenodeoxycholate (TCDC). Furthermore, genetic deletion of the PI3K gamma-isoform also decreased [Ca(2+)](i) responses to bile acids. Depletion of CCK-sensitive intracellular Ca(2+) pools or application of caffeine inhibited bile acid-induced [Ca(2+)](i) signals, indicating that bile acids release Ca(2+) from agonist-sensitive endoplasmic reticulum (ER) stores via an inositol (1,4,5)-trisphosphate-dependent mechanism. PI3K inhibitors increased the amount of Ca(2+) in intracellular stores during the exposure of acinar cells to bile acids, suggesting that PI3K negatively regulates SERCA-dependent Ca(2+) reloading into the ER. Bile acids inhibited Ca(2+) reloading into ER in permeabilized acinar cells. This effect was augmented by phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), suggesting that both bile acids and PI3K act synergistically to inhibit SERCA. Furthermore, inhibition of PI3K by LY-294002 completely inhibited trypsinogen activation caused by the bile acid TLC-S. Our results indicate that PI3K and its product, PIP(3), facilitate bile acid-induced [Ca(2+)](i) responses in pancreatic acinar cells through inhibition of SERCA-dependent Ca(2+) reloading into the ER and that bile acid-induced trypsinogen activation is mediated by PI3K. The findings have important implications for the mechanism of acute pancreatitis since [Ca(2+)](i) increases and trypsinogen activation mediate key pathological processes in this disorder.
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles Veterans Affairs Healthcare Center, Los Angeles, CA 90073, USA.
authors.forename: L
authors.initials: L
authors.lastname: Fischer
authors.forename: A S
authors.initials: AS
authors.lastname: Gukovskaya
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
authors.forename: O A
authors.initials: OA
authors.lastname: Mareninova
authors.forename: H
authors.initials: H
authors.lastname: Friess
authors.forename: I
authors.initials: I
authors.lastname: Gukovsky
authors.forename: S J
authors.initials: SJ
authors.lastname: Pandol
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002766:Cholecystokinin / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D046790:Pancreas, Exocrine / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013658:Taurolithocholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D001647:Bile Acids and Salts; D002118:Calcium; D002766:Cholecystokinin; D002867:Chromones; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015759:Ionomycin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013655:Taurochenodeoxycholic Acid; D013658:Taurolithocholic Acid; D019284:Thapsigargin; D000077191:Wortmannin; C066776:taurolithocholic acid 3-sulfate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one