Supramaximal CCK and CCh concentrations abolish VIP potentiation by inhibiting adenylyl cyclase activity

Abstract

Exocrine pancreatic secretion stimulated by vasoactive intestinal polypeptide (VIP), which acts through the adenylyl cyclase-cAMP pathway, is potentiated by stimulation with other secretagogues such as CCK and carbachol (CCh). However, the potentiating effect is abolished by the same secretagogues at supramaximal concentrations. In the present study, we examined the mechanisms by which supramaximal concentrations of CCK octapeptide (CCK-8) or CCh reduce the VIP-induced potentiation of amylase secretion from isolated rat pancreatic acini. VIP-stimulated amylase secretion was potentiated by submaximal stimulatory concentrations of CCK-8 and CCh but was reduced by the same reagents at higher concentrations. Supramaximal concentrations of CCK-8 or CCh also reduced forskolin-induced potentiation of amylase release but did not reduce that induced by 8-bromo-cAMP. Moreover, supramaximal concentrations of CCK-8 or CCh inhibited VIP-stimulated intracellular cAMP production as well as adenylyl cyclase activity. 12- O-tetradecanoylphorbol 13-acetate (TPA) also reduced the magnitude of the potentiation of amylase release caused by VIP plus CCK-8 or CCh, although TPA itself decreased neither VIP-stimulated adenylyl cyclase activity nor intracellular cAMP accumulation. These results indicate that supramaximal concentrations of CCK-8 and CCh reduce the potentiating effect of VIP and forskolin on amylase secretion by inhibiting the adenylyl cyclase activity. In addition, protein kinase C is suggested to be partly implicated in this inhibitory mechanism. The mechanisms that lead to such inhibition may be interlinked but distinct from each other.

Effects of the type of dietary fat on acetylcholine-evoked amylase secretion and calcium mobilization in isolated rat pancreatic acinar cells

“…Basal values in OO and C rats were similar between them and comparable to those described in the literature [29,30]. This contrasts with the results of basal Ca 2+ concentration.…”

“…The dose-response curve for ACh-induced amylase release in pancreatic acinar cells is typically bell-shaped, reaching a maximum at around 1 AM [29,34]. We also observed the strongest secretory effect at 1 AM ACh in both groups.…”

Protein kinase D1 mediates NF-κB activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells

“…CCK-8 or CCh induced PKD1 phosphorylation and activation at the concentration as low as 0.1 nM or 1 M, respectively, a physiological level of CCK-8 or CCh that causes maximal digestive enzyme secretion. The maximal effects of these agonists on PKD1 were achieved at 10 -100 nM CCK-8 or at 100 -1,000 M CCh, i.e., at their supramaximal concentrations that cause inhibition of enzyme secretion and activation of the inflammatory response (2,8,9,51). These results indicate that PKD1 is activated by CCK-8 and CCh at both physiological and pathological doses.…”

Adenylyl cyclases in the digestive system

“…A later study demonstrated that PKA is responsible for the modulation of Ca 2+ - and PKC-evoked amylase secretion in permeabilized rat pancreatic secretion [4]. Supramaximal concentrations of CCK or carbachol, by contrast, abolish VIP potentiation by inhibiting AC activity through activation of PKC [58]. …”

“…In the past years, the hypothesized AC expression profile in pancreatic exocrine cells came primary from studies that use pharmacologic stimulators and inhibitors of intracellular signals [58,59]. Recently, the expression profile of the transmembrane AC isoforms in intact mouse pancreas, isolated pancreatic acini and sealed duct fragments was establishsed [36].…”