Regulation of Physiologic and Pathologic Exocytosis in Pancreatic Acinar Cells

Abstract

The pancreatic acinar cell is one of the beststudied cell models of regulated secretion. On activation by neural or hormonal secretagogues, pancreatic acinar cells secrete a variety of inactive digestive enzyme precursors from zymogen granules (ZGs) undergoing exocytosis at the apical pole of this polarized cell. The acinar cell is also an excellent model to study pathologic membrane fusion events which underlie clinical pancreatitis. This includes apical exocytotic blockade along with ectopic fusion events including formation of large cytoplasmic vacuoles and redirected exocytosis to the basolateral plasma membrane; in these compartments zymogens become prematurely activated to initiate pancreatic tissue injury. Over the past two decades, my laboratory has been exploring the central role of SNARE [Soluble Nethylmaleimide-sensitive factor (NSF) Attachment Protein (SNAP) Receptors] proteins in regulating physiologic and pathologic fusion events in the pancreatic acinar cell. SNARE proteins on cognate vesicles (v-SNARE) and target membrane (t-SNARE) mediate membrane fusion by their highly interactive coiled domains called SNARE motifs that form a trans-complex facilitated by Sec1/Munc18 (SM) and other accessory proteins. This forces the secretory granule (ZG) to come in proximity to the target membrane (plasma membrane) by the zippering action of the trans-SNARE complex that culminates in membrane fusion. This review provides an overview on how these proteins mediate normal regulated exocytosis in the pancreatic acinar cell and pathologic fusion events underlying pancreatitis.