title: Supramaximal cholecystokinin displaces Munc18c from the pancreatic acinar basal surface, redirecting apical exocytosis to the basal membrane.
abstract: Exocytosis at the apical surface of pancreatic acinar cells occurs in the presence of physiological concentrations of cholecystokinin (CCK) but is inhibited at high concentrations. Here we show that Munc18c is localized predominantly to the basal membranes of acinar cells. Supramaximal but not submaximal CCK stimulation caused Munc18c to dissociate from the plasma membrane, and this displacement was blocked by protein kinase C (PKC) inhibitors. Conversely, whereas the CCK analog CCK-OPE alone failed to displace Munc18c from the membrane, this agent caused Munc18c displacement following minimal PKC activation. To determine the physiological significance of this displacement, we used the fluorescent dye FM1-43 to visualize individual exocytosis events in real-time from rat acinar cells in culture. We showed that supramaximal CCK inhibition of secretion resulted from impaired apical secretion and a redirection of exocytic events to restricted basal membrane sites. In contrast, CCK-OPE evoked apical exocytosis and could only induce basolateral exocytosis following activation of PKC. Infusion of supraphysiological concentrations of CCK in rats, a treatment that induced tissue changes reminiscent of mild acute pancreatitis, likewise resulted in rapid displacement of Munc18c from the basal membrane in vivo.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada. herbert.gaisano@utoronto.ca
authors.forename: H Y
authors.initials: HY
authors.lastname: Gaisano
authors.forename: M P
authors.initials: MP
authors.lastname: Lutz
authors.forename: J
authors.initials: J
authors.lastname: Leser
authors.forename: L
authors.initials: L
authors.lastname: Sheu
authors.forename: G
authors.initials: G
authors.lastname: Lynch
authors.forename: L
authors.initials: L
authors.lastname: Tang
authors.forename: Y
authors.initials: Y
authors.lastname: Tamori
authors.forename: W S
authors.initials: WS
authors.lastname: Trimble
authors.forename: A M
authors.initials: AM
authors.lastname: Salapatek
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002766:Cholecystokinin / Q000378:metabolism / Q000494:pharmacology*; D005089:Exocytosis; D008565:Membrane Proteins / Q000378:metabolism; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D010179:Pancreas / Q000378:metabolism*; D010195:Pancreatitis / Q000209:etiology; D011493:Protein Kinase C / Q000502:physiology; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D050600:SNARE Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D033921:Vesicular Transport Proteins
chemical_list: D008565:Membrane Proteins; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D050600:SNARE Proteins; C497944:Stxbp3 protein, rat; D033921:Vesicular Transport Proteins; D002766:Cholecystokinin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate