Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells

Gastroenterology. 2008 Aug;135(2):632-41. doi: 10.1053/j.gastro.2008.05.026. Epub 2008 May 7.


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 Ca(2+), 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 Ca(2+) ion concentration, showing apical to basal progression, in acinar cells from 14 patients with unobstructed pancreata. The cytosolic Ca(2+) ion concentration increases were followed by increases in mitochondrial adenosine triphosphate production and secretion. CCK-elicited Ca(2+) signals and exocytosis were not inhibited by atropine (1 mumol/L) or tetrodotoxin (100 nmol/L), showing that CCK was unlikely to have acted via neurotransmitter release. CCK-elicited Ca(2+) signals were inhibited reversibly by caffeine (5-20 mmol/L), indicating involvement of intracellular inositol trisphosphate receptor Ca(2+) release channels. Acetylcholine (50 nmol/L) elicited similar Ca(2+) signals.

Conclusions: CCK at physiologic concentrations in the presence of atropine and tetrodotoxin elicits cytosolic Ca(2+) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylcholine / pharmacology
  • Adenosine Triphosphate / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Amylases / metabolism*
  • Anesthetics, Local / pharmacology
  • Aniline Compounds
  • Atropine / pharmacology
  • Caffeine / pharmacology
  • Calcium Signaling* / drug effects
  • Cell Polarity
  • Cholecystokinin / metabolism*
  • Cholinergic Agents / pharmacology
  • Cytosol / metabolism*
  • Exocytosis* / drug effects
  • Female
  • Fluorescent Dyes
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Mitochondria / metabolism
  • Muscarinic Antagonists / pharmacology
  • NAD / metabolism
  • Pancreas, Exocrine / cytology
  • Pancreas, Exocrine / drug effects
  • Pancreas, Exocrine / enzymology
  • Pancreas, Exocrine / metabolism*
  • Quinacrine / pharmacology
  • Sincalide / metabolism
  • Tetrodotoxin / pharmacology
  • Time Factors
  • Xanthenes


  • Anesthetics, Local
  • Aniline Compounds
  • Cholinergic Agents
  • Fluo 4
  • Fluorescent Dyes
  • Inositol 1,4,5-Trisphosphate Receptors
  • Muscarinic Antagonists
  • Xanthenes
  • NAD
  • Caffeine
  • Tetrodotoxin
  • Atropine
  • cholecystokinin 58
  • Adenosine Triphosphate
  • Cholecystokinin
  • Amylases
  • Quinacrine
  • Sincalide
  • Acetylcholine