Pancreatic protease activation by alcohol metabolite depends on Ca²⁺ release via acid store IP₃ receptors
2009
Gerasimenko, Julia V. | Lur, György | Sherwood, Mark W. | Ebisui, Etsuko | Tepikin, Alexei V. | Mikoshiba, Katsuhiko | Gerasimenko, Oleg V. | Petersen, Ole H.
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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