Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 26, Pages 10758-10763Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904818106
Keywords
calcium; inositol trisphopshate receptors; pancreatitis
Categories
Funding
- Medical Research Council (MRC)
- Japanese Science and Technology Agency Calcium Oscillation
- Medical Research Council [G0300076, G0700167, G9900432] Funding Source: researchfish
- MRC [G9900432, G0700167, G0300076] Funding Source: UKRI
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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 (IP(3)Rs) of types 2 and 3. POAEE evoked very little Ca2+ release and trypsin activation when IP(3)Rs of both types 2 and 3 were knocked out. Antibodies against IP(3)Rs of types 2 and 3, but not type 1, markedly inhibited POAEE-elicited Ca2+ release and trypsin activation. We conclude that Ca2+ release through IP(3)Rs 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.
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