Low concentrations of protein kinase C-activating agonists suppress cholecystokinin-OPE-evoked Ca2+ mobilization in rat pancreatic acini.

Abstract

The phenethyl ester analogues of cholecystokinin, OPE and JMV-180, are fully efficacious rat pancreatic secretagogues which, unlike cholecystokinin (CCK), do not elicit supramaximal inhibition of secretion, and stimulate a sustained rise of cytosolic calcium ([Ca2+]i) above basal levels. We have recently shown that low-level protein kinase C (PKC) activation by preincubation of acini with 1 nM 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or minimally secreting concentrations of PKC-activating receptor agonists (1 pM CCK-8, 0.1 microM carbachol or 10 pM bombesin) cause supramaximal inhibition of OPE-stimulated enzyme secretion. We now show that treatment of acini under these conditions also suppresses the sustained rise of [Ca2+]i stimulated by OPE to basal levels in these cells, without changing the initial OPE-stimulated [Ca2+]i peak. The resultant pattern of calcium signalling is similar to that evoked by supramaximal concentrations of native CCK. This suggests that even low concentrations of PKC-activating agonists have the potential to induce inhibitory effects on Ca2+ mobilization and that this kinase is important in generating the supramaximal inhibition observed in response to CCK.