Mutual dependence of VIP/PACAP and CCK receptor signaling for a physiological role in duck exocrine pancreatic secretion

Abstract

Unlike in rodents, CCK has not been established as a physiological regulator in avian exocrine pancreatic secretion. In the isolated duck pancreatic acini, 1 nM CCK was required for stimulation of amylase secretion, maximal effect being achieved at 10 nM; picomolar CCK was without effect. Vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase activating peptide (PACAP) receptor (VPAC) agonists PACAP-38 and PACAP-27 (10-12-10-7 M) alone had no effect, but made picomolar CCK effective. VPAC agonist VIP 10-10-10-7 M stimulated amylase secretion marginally, but made CCK 10-12-10-10 M effective also. PACAP-27 and VIP both shifted the maximal CCK concentration from 10-8 to 10-9 M. This sensitizing effect was mimicked by forskolin. CCK dose dependently induced intracellular Ca2+ concentration ([Ca2+]i) oscillations. PACAP-38 (1 nM), PACAP-27 (1 nM), VIP (10 nM), or forskolin (10 μM) alone did not stimulate [Ca2+]i increase, neither did they modulate CCK (1 nM)-induced oscillations; but when they were added to cells simultaneously exposed to subthreshold CCK (10 pM), calcium spikes emerged. Amylase secretion induced by the simultaneous presence of 10 pM CCK and VPAC agonists was completely blocked by removing extracellular calcium, but the protein kinase C inhibitor staurosporine (1 μM) was without effect. CCK (10 nM)-induced secretion was inhibited by CCK1 receptor antagonist FK480 (1 μM). Gastrin from 10-12 to 10-6 M did not stimulate amylase secretion nor did it (100 nM) induce [Ca2+]i increase. The above data suggest that duck pancreatic acini possess both CCK1 and VPAC receptors; simultaneous activation of both is required for each to play a physiological role.

How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans

“…Redrawn from data published in Ref. 149. B: low, physiological concentrations of CCK alone do not stimulate amylase secretion in freshly isolated duck pancreatic acini; only when CCK concentration reaches supraphysiological levels will it have a stimulatory effect on amylase secretion, with a maximal stimulatory concentration of 10 nM (solid blue line).…”

“…Further examination of the dose-response curve revealed that rodent CCK1Rs are exceptionally sensitive to CCK, with a threshold concentration at 1 pM (23,57,115,149). Picomolar CCK concentrations induced significant amylase secretion in all isolated rodent (rat, mouse, and guinea pig) pancreatic acini, and maximal stimulating CCK concentration was 100 pM (149).…”

“…Duodenal infusion of casein, for example, resulted in elevation of plasma CCK from fasting levels of 0.5 Ϯ 0.1 to 3.8 Ϯ 0.4 pM (72). This picomolar postprandial plasma CCK concentration is sufficient to stimulate enzyme secretion and trigger Ca 2ϩ oscillation in rat pancreatic acini (2,(21)(22)(23)149). Soya proteins and amino acid mixtures mimicking soya protein composition could increase gut CCK release in chicks (150).…”

“…This has led to the belief that endogenous CCK does not have any important role in digestive enzyme secretion from exocrine pancreas in birds (35,36,98,125 (149). These data suggest that duck pancreatic acini possess both CCK1 and VPAC receptors and that simultaneous activation of both is required for each to play a physiological role (149) (Fig.…”

“…This general picture has been changed drastically by the recent findings that CCK can also stimulate exocrine pancreatic secretion by the excitation of sensory nerves and vagovagal and enteropancreatic reflexes, and this may be the only pathway in humans (65, 105). In addition, major differences have been found in the traditional humoral pathway, depending on the animal species (35,149). Therefore, the purpose of this review is to present the current status of CCK regulation of exocrine pancreatic secretion with a particular emphasis on species specificity as shown in birds, rodents, and humans.…”