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

Gerasimenko, Julia Vladimirovna ORCID: https://orcid.org/0000-0002-2262-2543, Lur, György, Sherwood, Mark W., Ebisui, Etsuko, Tepikin, Alexei V., Mikoshiba, Katsuhiko, Gerasimenko, Oleg Vsevolodovich ORCID: https://orcid.org/0000-0003-2573-8258 and Petersen, Ole Holger ORCID: https://orcid.org/0000-0002-6998-0380 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:	Schools > Biosciences Research Institutes & Centres > 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:	02 Dec 2022 11:58
URI:	https://orca.cardiff.ac.uk/id/eprint/9131

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