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J. Biol. Chem., Vol. 282, Issue 17, 13047-13058, April 27, 2007

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Alcohol/Cholecystokinin-evoked Pancreatic Acinar Basolateral Exocytosis Is Mediated by Protein Kinase C Phosphorylation of Munc18c^*

Laura I. Cosen-Binker, Patrick P. L. Lam¹, Marcelo G. Binker, Joseph Reeve, Stephen Pandol, and Herbert Y. Gaisano²

From the Departments of Medicine and Physiology, University Health Network, University of Toronto, Toronto, Ontario M5S 1A8, Canada and the Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073

The pancreatic acinus is the functional unit of the exocrine pancreas whose role is to secrete zymogens into the gut lumen for food digestion via apical exocytosis. We previously reported that supramaximal CCK induced apical blockade and redirected exocytosis to ectopic sites on the basolateral plasma membrane (BPM) of this polarized cell, leading to pancreatitis. Basolateral exocytosis was mediated by protein kinase C phosphorylation of BPM Munc18c, causing its displacement into the cytosol and activation of BPM-bound Syntaxin-4 to form a SNARE complex. To mimic the conditions of alcoholic pancreatitis, we now examined whether 20 mM alcohol followed by submaximal CCK might mimic supramaximal CCK in inducing these pathologic exocytotic events. We show that a non-secretory but clinically relevant alcohol concentration (20 mM) inhibited submaximal CCK (50 pM)-stimulated amylase secretion by blocking apical exocytosis and redirecting exocytosis to less efficient BPM, indeed mimicking supramaximal CCK (10 nM) stimulation. We further demonstrate that basolateral exocytosis caused by both stimulation protocols is mediated by PKC-induced phosphorylation of Munc18c: 1) PKC is activated, which binds and induces phosphorylation of PM-Munc18c at a Thr site, and these events can be inhibited by PKC blockade; 2) PKC inhibition blocks Munc18c displacement from the BPM; 3) PKC inhibition prevents basolateral exocytosis but does not rescue apical exocytosis. We conclude that 20 mM alcohol/submaximal CCK as well supramaximal CCK stimulation can trigger pathologic basolateral exocytosis in pancreatic acinar cells via PKC-mediated activation of Munc18c, which enables Syntaxin-4 to become receptive in forming a SNARE complex in the BPM; and we further postulate this to be an underlying mechanism contributing to alcoholic pancreatitis.

Received for publication, December 5, 2006 , and in revised form, February 6, 2007.

^* This work was supported in part by Grant R21 AA015579-01A1 (to H. Y. G.) from the National Institutes of Health, the Alcohol Beverage Medical Research Foundation, and an equipment grant from the Banting and Best Diabetes Center (University of Toronto). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ Funded by graduate doctoral studentships from the Canadian Digestive Health Foundation and Canadian Institute of Health Research.

² To whom correspondence should be addressed: University of Toronto, Rm. 7226, Medical Science Bldg., 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-1526; Fax: 416-978-8765; E-mail: herbert.gaisano{at}utoronto.ca.

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