Journal of Biological Chemistry
Volume 280, Issue 7, 18 February 2005, Pages 5430-5434
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Protein Synthesis, Post-Translation Modification, and Degradation
Vacuolar ATPase Regulates Zymogen Activation in Pancreatic Acini*

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Supramaximal concentrations of cholecystokinin or its analogue caerulein have been shown to stimulate the proteolytic activation of zymogens within the pancreatic acinar cell and initiate acute pancreatitis. Previous studies suggest that a low pH compartment might be required for activation. To test this hypothesis, the effects of agents that modulate intracellular pH on caerulein-induced trypsin and chymotrypsin activation were studied. Pretreatment of pancreatic acini with the proto-ionophore monensin (10 μm) and the weak base chloroquine (40 μm) inhibited activation. Pre-incubation with the vacuolar ATPase (V-ATPase) inhibitors bafilomycin A1 and concanamycin A also decreased activation in a concentration-dependent manner with 50% inhibition at ∼50 and 25 nm, respectively. Caerulein stimulation caused a time- and concentration-dependent translocation of soluble V-ATPase V1 subunits to a membrane fraction, a marker of V-ATPase activation. Carbachol also stimulated translocation at supramaximal concentrations. Elevation of cytosolic Ca2+ by thapsigargin was sufficient to induce translocation. Thus, stimulation of V-ATPase activity appears to be required for agonist-induced zymogen activation in the pancreatic acinar cell.

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*

This work was supported by a Goldwater Student Research Award (to S. D. W.), a Veterans Administration Senior Career Development Award (to F. S. G.), and National Institutes of Health Grant RO1 DK54021 (to F. S. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.