Pancreatic protease activation by alcohol metabolite depends on Ca2+ release via acid store IP3 receptors |
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Authors: | Julia V Gerasimenko Gy?rgy Lur Mark W Sherwood Etsuko Ebisui Alexei V Tepikin Katsuhiko Mikoshiba Oleg V Gerasimenko Ole H Petersen |
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Institution: | aMedical Research Council Group, Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, L69 3BX, United Kingdom; and ;bLaboratory for Developmental Neurobiology, Riken Brain Science Institute, 2-1 Hirosawa, Wako City, Saitama, 351-0198 Japan |
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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. |
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Keywords: | calcium inositol trisphopshate receptors pancreatitis |
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