Phosphatidylinositol 3-kinase facilitates bile acid-induced Ca2+responses in pancreatic acinar cells

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Abstract
Bile acids are known to induce Ca2+signals in pancreatic acinar cells. We have recently shown that phosphatidylinositol 3-kinase (PI3K) regulates changes in free cytosolic Ca2+concentration ([Ca2+]i) elicited by CCK by inhibiting sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA). The present study sought to determine whether PI3K regulates bile acid-induced [Ca2+]iresponses. In pancreatic acinar cells, pharmacological inhibition of PI3K with LY-294002 or wortmannin inhibited [Ca2+]iresponses to taurolithocholic acid 3-sulfate (TLC-S) and taurochenodeoxycholate (TCDC). Furthermore, genetic deletion of the PI3K γ-isoform also decreased [Ca2+]iresponses to bile acids. Depletion of CCK-sensitive intracellular Ca2+pools or application of caffeine inhibited bile acid-induced [Ca2+]isignals, indicating that bile acids release Ca2+from agonist-sensitive endoplasmic reticulum (ER) stores via an inositol ( 1 , 4 , 5 )-trisphosphate-dependent mechanism. PI3K inhibitors increased the amount of Ca2+in intracellular stores during the exposure of acinar cells to bile acids, suggesting that PI3K negatively regulates SERCA-dependent Ca2+reloading into the ER. Bile acids inhibited Ca2+reloading into ER in permeabilized acinar cells. This effect was augmented by phosphatidylinositol ( 3 , 4 , 5 )-trisphosphate (PIP3), 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, PIP3, facilitate bile acid-induced [Ca2+]iresponses in pancreatic acinar cells through inhibition of SERCA-dependent Ca2+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 [Ca2+]iincreases and trypsinogen activation mediate key pathological processes in this disorder.