Zymogen secretory granules in pancreatic acinar cells express two vesicle associated membrane proteins (VAMP), VAMP2 and 8, each controlling 50% of stimulated secretion. Analysis of secretion kinetics identified a first−phase (0 − 2 min) mediated by VAMP2, and second− (2 − 10 min) and third−phases (10− 30 min) mediated by VAMP8. Induction of acinar pancreatitis by supramaximal cholecystokinin (CCK−8) stimulation inhibits VAMP8−mediated second− and third−phase, but not VAMP2−mediated first-phase secretion. Elevation of cAMP during supramaximal CCK-8 mitigates third−phase secretory inhibition and acinar damage caused by the accumulation of prematurely activated trypsin. VAMP8−/− acini are resistant to secretory inhibition by supramaximal CCK−8, and in spite of a 4.5 fold increase in total cellular trypsinogen levels, are fully protected from intracellular trypsin accumulation and acinar damage. VAMP8-mediated secretion is dependent on expression of the early endosomal proteins Rab5, D52 and EEA1. Supramaximal CCK−8 (60 min) caused a 60% reduction in the expression of D52 followed by Rab 5 and EEA1 in isolated acini and in in vivo. The loss of D52 occurred as consequence of its entry into autophagic vacuoles and was blocked by lysosomal cathepsin B and L inhibition. Accordingly, adenoviral overexpression of Rab5 or D52 enhanced secretion in response to supramaximal CCK−8 and prevented accumulation of activated trypsin. These data support that acute inhibition of VAMP8-mediated secretion during pancreatitis triggers intracellular trypsin accumulation and the loss of the early endosomal compartment. Maintaining anterograde endosomal trafficking during pancreatitis maintains VAMP8−dependent secretion thereby preventing accumulation of activated trypsin.
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