Intracellular Signaling Mechanisms Activated by Cholecystokinin-Regulating Synthesis and Secretion of Digestive Enzymes in Pancreatic Acinar Cells

Abstract

The intracellular signaling mechanisms by which cholecystokinin (CCK) and other secretagogues regulate pancreatic acinar function are more complex than originally realized. CCK couples through heterotrimeric G proteins of the Gq family to lead to an increase in intracellular free Ca2+, which shows spatial and temporal patterns of signaling. The actions of Ca2+ are mediated in part by activation of a number of Ca2+-activated protein kinases and the protein phosphatase calcineurin. By the process of exocytosis the intracellular messengers Ca2+, diacylglycerol, and cAMP activate the release of the zymogen granule content in a manner that is poorly understood. This fusion event most likely involves SNARE and Rab proteins present on zymogen granules and cellular membrane domains. More likely related to nonsecretory aspects of cell function, CCK also activates three MAPK cascades leading to activation of ERKs, JNKs, and p38 MAPK. Although the function of these pathways is not well understood, ERKs are probably related to cell growth, and through phosphorylation of hsp27, p38 can affect the actin cytoskeleton. The PI3K (phosphatidylinositol 3-kinase)-mTOR (mammalian target of rapamycin) pathway is important for regulation of acinar cell protein synthesis because it leads to both activation of p70S6K and regulation of the availability of eIF4E in response to CCK. CCK also activates a number of tyrosyl phosphorylation events including that of p125FAK and other proteins associated with focal adhesions.

Phosphospecific Site Tyrosine Phosphorylation of p125FAK and Proline-rich Kinase 2 Is Differentially Regulated by Cholecystokinin Receptor Type A Activation in Pancreatic Acini

“…The degree of participation of the two CCK A receptor affinity states in the site-specific phosphorylation in FAK and PYK2 has both similarities and differences from that reported with CCK A receptorstimulated tyrosine phosphorylation of other proteins in pancreatic acini. CCK A receptor activation in rat pancreatic acini has been shown to cause tyrosine phosphorylation of paxillin (19), p130 Cas (29), PKC-␦ (22), Jun kinase (69), and mitogenactivated protein kinase (52). Similar to our results in the present study for FAK and PYK2 phosphospecific site phosphorylation, stimulation of tyrosine phosphorylation of paxillin in rat pancreatic acini by CCK was stimulated by activation of both the high and the low CCK A receptor states.…”

“…In pancreatic acini activation of CCK A receptors stimulates rapid tyrosine phosphorylation of both FAK (34) and PYK2 (9). Furthermore, its intracellular signaling cascades have been extensively studied and shown to involve stimulation of phospholipase C with mobilization of cellular calcium and PKC activation, activation of phospholipase D and phospholipase A 2 , and stimulation of multiple tyrosine kinase cascades (10,25,52). The effect of CCK in pancreatic acini is therefore an excellent potential model to use to assess the ability of an agonist to stimulate tyrosine phosphorylation of both FAK-and PYK2-specific sites and to investigate the role of changes in [Ca 2ϩ ] i and PKC activation in mediating these effects in the same cell.…”

Physiological parameters governing the action of pancreatic lipase

“…These processes are discussed in greater detail elsewhere (27,29) . While the intracellular pathways involved in pancreatic enzyme release (including protein sorting and zymogen granule binding) are not fully understood (27,28) , a number of pathways have been suggested for control of the luminal factors relevant to lipolytic activity. While it is currently unsure whether the release of separate pancreatic enzymes is independent of each other or not (30) , CCK appears to be the main hormonal drive for increased zymogen secretion and, therefore, lipase secretion.…”

Noc2 is essential in normal regulation of exocytosis in endocrine and exocrine cells

“…Many nonneuronal cell types such as endocrine and exocrine cells contain secretory vesicles identified as dense-core granules, the contents of which exert a variety of biological effects (3). Secretory vesicle exocytosis occurs in the secretion of hormones in amine͞peptide-containing endocrine cells (4,5) and digestive enzymes in exocrine cells (6). Rab3 is a subfamily of the small GTP-binding protein Rab family (7), and plays an important role in targeting, docking, priming, and fusion processes in exocytosis (8).…”