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This Article Full Text Full Text (PDF) Corrigendum All Versions of this Article: 292/3/G875    most recent 00558.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in AJP - GI Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Fischer, L. Articles by Pandol, S. J. Search for Related Content PubMed PubMed Citation Articles by Fischer, L. Articles by Pandol, S. J.

HORMONES AND SIGNALING

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

¹Veterans Affairs Greater Los Angeles Healthcare System and ²Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California; ³Department of Surgery, University of Heidelberg, Germany; and ⁴Institute for Molecular Biotechnology, Austrian Academy of Sciences, Vienna, Austria

Submitted 9 December 2005 ; accepted in final form 1 November 2006

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⁺]_i responses. In pancreatic acinar cells, pharmacological inhibition of PI3K with LY-294002 or wortmannin inhibited [Ca²⁺]_i responses to taurolithocholic acid 3-sulfate (TLC-S) and taurochenodeoxycholate (TCDC). Furthermore, genetic deletion of the PI3K -isoform also decreased [Ca²⁺]_i responses to bile acids. Depletion of CCK-sensitive intracellular Ca²⁺ pools or application of caffeine inhibited bile acid-induced [Ca²⁺]_i signals, 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⁺]_i responses 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⁺]_i increases and trypsinogen activation mediate key pathological processes in this disorder.

sarco(endo)plasmic reticulum Ca²⁺-ATPase; taurolithocholic acid 3-sulfate; taurochenodeoxycholate; cholecystokinin; pancreatitis

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Corrigendum

AJP - GI 2007 292: G1815. [Full Text]  

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