HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 287/6/G1200    most recent 00212.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend 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 regulates Ca²⁺ signaling in pancreatic acinar cells through inhibition of sarco(endo)plasmic reticulum Ca²⁺-ATPase

¹Veterans Affairs Greater Los Angeles Healthcare System and ²Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90073; ³Department of Surgery, University of Heidelberg, 69120 Heidelberg, Germany; and ⁴Institute for Molecular Biotechnology, Austrian Academy of Sciences, A-1030 Vienna, Austria

Submitted 9 May 2004 ; accepted in final form 20 July 2004

Calcium is a key mediator of hormone-induced enzyme secretion in pancreatic acinar cells. At the same time, abnormal Ca²⁺ responses are associated with pancreatitis. We have recently shown that inhibition of phosphatidylinositol 3-kinase (PI3-kinase) by LY-294002 and wortmannin, as well as genetic deletion of PI3-kinase-, regulates Ca²⁺ responses and the Ca²⁺-sensitive trypsinogen activation in pancreatic acinar cells. The present study sought to determine the mechanisms of PI3-kinase involvement in Ca²⁺ responses induced in these cells by CCK and carbachol. The PI3-kinase inhibitors inhibited both Ca²⁺ influx and mobilization from intracellular stores induced by stimulation of acini with physiological and pathological concentrations of CCK, as well as with carbachol. PI3-kinase inhibition facilitated the decay of cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) oscillations observed in individual acinar cells. The PI3-kinase inhibitors decreased neither CCK-induced inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] production nor Ins(1,4,5)P₃-induced Ca²⁺ mobilization, suggesting that the effect of PI3-kinase inhibition is not through Ins(1,4,5)P₃ or Ins(1,4,5)P₃ receptors. PI3-kinase inhibition did not affect Ca²⁺ mobilization induced by thapsigargin, a specific inhibitor of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA). Moreover, SERCA blockade with thapsigargin abolished the effects of pharmacological and genetic PI3-kinase inhibition on [Ca²⁺]_i signals, suggesting SERCA as a downstream target of PI3-kinase. Both pharmacological PI3-kinase inhibition and genetic deletion of PI3-kinase- increased the amount of Ca²⁺ in intracellular stores during CCK stimulation. Finally, addition of the PI3-kinase product phosphatidylinositol 3,4,5-trisphosphate to permeabilized acini significantly attenuated Ca²⁺ reloading into the endoplasmic reticulum. The results indicate that PI3-kinase regulates Ca²⁺ signaling in pancreatic acinar cells through its inhibitory effect on SERCA.

pancreas; cholecystokinin; carbachol

This article has been cited by other articles:

				L. Fischer, A. S. Gukovskaya, J. M. Penninger, O. A. Mareninova, H. Friess, I. Gukovsky, and S. J. Pandol Phosphatidylinositol 3-kinase facilitates bile acid-induced Ca2+ responses in pancreatic acinar cells Am J Physiol Gastrointest Liver Physiol, March 1, 2007; 292(3): G875 - G886. [Abstract] [Full Text] [PDF]