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Pancreatic protease activation by alcohol metabolite depends on Ca2+ release via acid store IP3 receptors

Gerasimenko, Julia Vladimirovna, Lur, György, Sherwood, Mark W., Ebisui, Etsuko, Tepikin, Alexei V., Mikoshiba, Katsuhiko, Gerasimenko, Oleg Vsevolodovich and Petersen, Ole Holger 2009. Pancreatic protease activation by alcohol metabolite depends on Ca2+ release via acid store IP3 receptors. Proceedings of the National Academy of Sciences of the United States of America 106 (26) , pp. 10758-10763. 10.1073/pnas.0904818106

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Abstract

Toxic alcohol effects on pancreatic acinar cells, causing the often fatal human disease acute pancreatitis, are principally mediated by fatty acid ethyl esters (non-oxidative products of alcohol and fatty acids), emptying internal stores of Ca2+. This excessive Ca2+ liberation induces Ca2+-dependent necrosis due to intracellular trypsin activation. Our aim was to identify the specific source of the Ca2+ release linked to the fatal intracellular protease activation. In 2-photon permeabilized mouse pancreatic acinar cells, we monitored changes in the Ca2+ concentration in the thapsigargin-sensitive endoplasmic reticulum (ER) as well as in a bafilomycin-sensitive acid compartment, localized exclusively in the apical granular pole. We also assessed trypsin activity in the apical granular region. Palmitoleic acid ethyl ester (POAEE) elicited Ca2+ release from both the ER as well as the acid pool, but trypsin activation depended predominantly on Ca2+ release from the acid pool, that was mainly mediated by functional inositol 1,4,5- trisphosphate receptors (IP3Rs) of types 2 and 3. POAEE evoked very little Ca2+ release and trypsin activation when IP3Rs of both types 2 and 3 were knocked out. Antibodies against IP3Rs of types 2 and 3, but not type 1, markedly inhibited POAEE-elicited Ca2+ release and trypsin activation. We conclude that Ca2+ release through IP3Rs of types 2 and 3 in the acid granular Ca2+ store induces intracellular protease activation, and propose that this is a critical process in the initiation of alcohol-related acute pancreatitis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QP Physiology
Q Science > QR Microbiology
Uncontrolled Keywords: Calcium; inositol trisphopshate receptors; pancreatitis
Publisher: National Academy of Sciences
ISSN: 0027-8424
Last Modified: 03 Nov 2017 01:10
URI: http://orca.cf.ac.uk/id/eprint/9131

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