Direct Activation of Cytosolic Ca²⁺ Signaling and Enzyme Secretion by Cholecystokinin in Human Pancreatic Acinar Cells

Background & Aims: Cholecystokinin (CCK) has been thought to act only indirectly on human pancreatic acinar cells via vagal nerve stimulation, rather than by direct CCK receptor activation as on rodent pancreatic acinar cells. We tested whether CCK (CCK-8 and human CCK-58) can act directly on human pancreatic acinar cells. Methods: Human acinar cells were freshly isolated from pancreatic transection line samples, loaded with Fluo4-AM or quinacrine, and examined for Ca²⁺, metabolic and secretory responses to CCK-8, human CCK-58, or acetylcholine with confocal microscopy. Results: CCK-8 and human CCK-58 at physiologic concentrations (1-20 pmol/L) elicited rapid, robust, oscillatory increases of the cytosolic Ca²⁺ ion concentration, showing apical to basal progression, in acinar cells from 14 patients with unobstructed pancreata. The cytosolic Ca²⁺ ion concentration increases were followed by increases in mitochondrial adenosine triphosphate production and secretion. CCK-elicited Ca²⁺ signals and exocytosis were not inhibited by atropine (1 μmol/L) or tetrodotoxin (100 nmol/L), showing that CCK was unlikely to have acted via neurotransmitter release. CCK-elicited Ca²⁺ signals were inhibited reversibly by caffeine (5-20 mmol/L), indicating involvement of intracellular inositol trisphosphate receptor Ca²⁺ release channels. Acetylcholine (50 nmol/L) elicited similar Ca²⁺ signals. Conclusions: CCK at physiologic concentrations in the presence of atropine and tetrodotoxin elicits cytosolic Ca²⁺ signaling, activates mitochondrial function, and stimulates enzyme secretion in isolated human pancreatic acinar cells. We conclude that CCK acts directly on acinar cells in the human pancreas.