The pathological activation of proteases within the pancreatic acinar cell is critical to initiating pancreatitis. Stimulation of acinar cells with supraphysiological concentrations of the CCK analog caerulein (CER) leads to protease activation and pancreatitis. Agents that sensitize the acinar cell to the effects of CCK might contribute to disease. The effects of physiological ligands that increase acinar cell cAMP [secretin, VIP, and pituitary adenylate cyclase activating peptide (PACAP)] on CER-induced responses were examined in isolated rat pancreatic acini. Each ligand sensitized the acinar cell to zymogen activation by physiological concentrations of CER (0.1 nM). VIP and PACAP but not secretin also enhanced activation by supraphysiological concentrations of CER (0.1 μM). A cell-permeable cAMP analog also sensitized the acinar cell to CER-induced activation. The cAMP antagonist Rp-8-Br-cAMP inhibited these sensitizing effects. These findings suggest that ligands that increase acinar cell cAMP levels can sensitize the acinar cell to the effects of CCK-induced zymogen activation.
Keywordscaerulein; chymotrypsin; secretin; trypsin THE PREMATURE ACTIVATION of digestive zymogens within the pancreatic acinar cell contributes to the initiation of pancreatitis. In the rodent pancreas, ligands such as CCK or the muscarinic agonist carbachol can cause zymogen activation in isolated pancreatic acini. These ligands activate specific G protein-linked receptors that stimulate phospholipase C and increase cytosolic Ca 2+ . Several reports (7,9) have observed that zymogen activation within the acinar cell requires an increase in cytosolic Ca 2+ . CCK-induced activation depends on the presence of extracellular Ca 2+ and an increase in cytosolic Ca 2+ (9). Removal of extracellular Ca 2+ or chelation of intracellular Ca 2+ blocks caerulein (a CCK homolog)-induced trypsin activation (7,9). Whether an increase in intracellular Ca 2+ alone is sufficient to cause activation is controversial. Increasing cytosolic Ca 2+ by thapsigargin was found to cause zymogen activation in one study but not in another (7,9). Thus additional signaling pathways may act independently or with Ca 2+ to cause zymogen activation.The pancreatic acinar cell has receptors for pathways that are coupled to increasing both cytosolic Ca 2+ and cAMP. Stimulation of acinar cell CCK or muscarinic receptors is linked to increased cytosolic Ca 2+ . Secretin, pituitary adenylate cyclase activating peptide (PACAP), and VIP stimulate receptors that are primarily coupled to cAMP generation. However, some 2+ and cAMP (5). Moreover, although physiological concentrations of CCK do not cause a measurable increase in cAMP, they do activate cAMP-dependent protein kinase (5). Similarly, secretin has been reported in some but not all studies to not only increase cellular cAMP, but to also stimulate phospholipase C activity causing an increase in cytosolic Ca 2+ in the acinar cell (10,12). Because ligands that increase both acinar cell Ca 2+ and cAMP are released in...