Much is known about the downstream events leading to experimental acute pancreatitis. However, neither acute nor chronic alcohol treatment could independently induce these downstream events to actually cause damage to the exocrine pancreas! The current consensus is that alcohol induces undefined upstream 'susceptibility' factors, which in the presence of downstream triggering events, then lead to pancreatic injury. The precise susceptibility factor(s) activated by alcohol in exocrine pancreas is however unknown. Our long-term goal is to elucidate the underlying alcohol-induced susceptibility factors predisposing to pancreatitis. Using a fluorescent imaging assays, we visualized in real time that supramaximal CCK stimulation redirected exocytosis normally occurring at the apical plasma membrane (PM) surface to the basolateral surface. The underlying molecular mechanism of the basolateral exocytosis involves a complex of SNARE proteins: Munc18c/Syn-4/SNAP23/VAMP, whereby high CCK caused Munc18c to dissociate from Syntaxin4 on the basolateral PM. This relieves basolateral PM-Syn-4 to then bind SNAP-23 and zymogen granule VAMP to form the SNARE exocytic complex which consummates exocytosis. This mechanism also played a role in supramaximal CCK-induced rat acute pancreatitis. We now HYPOTHESIZE that alcohol participates in evoking excess exocytosis at the basolateral PM, by inducing Munc18c to become displaced from Syn-4 at the basolateral PM into the cytosol. This susceptibility mechanism in part via PKC pathways induced by alcohol renders the basolateral PM surface receptive to pathological exocytosis, which we will examine in Aim 1. The resulting excess in ectopic release of digestive enzymes into the interstitial space, when not efficiently cleared by the micro-circulation, become activated to cause pancreatic tissue injury which we will examine in an alcohol diet pancreatitis model in Aim 2. Significance: These actions of alcohol on pancreatic acinar PM-Munc18c may be the 'sentinel' event that initiates the role of alcohol in pancreatic injury, and which could be therapeutically targeted.