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Am J Physiol Gastrointest Liver Physiol (October 8, 2009). doi:10.1152/ajpgi.00119.2009
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Research Article

Cholecystokinin-58 and cholecystokinin-8 exhibit similar actions on calcium signalling, zymogen secretion and cell fate in murine pancreatic acinar cells

David Neil Criddle,1,* David Booth,1 Rajarshi Mukherjee,1 Euan McLaughlin,1 Gary M. Green,2 Robert Sutton,1 Ole H Petersen,3 and Joseph R Reeve, Jr.4

1University of Liverpool 2University of Texas Health Science Center 3Liverpool University 4CURE: Digestive Diseases Research Center

Submitted 25 March 2009 ; revision received 17 September 2009 ; accepted in final form 5 October 2009

ABSTRACT

The gastrointestinal hormone cholecystokinin (CCK) exists in various molecular forms, with differences in bioactivity between the well-characterised CCK-8 and larger CCK-58 previously reported. We have compared the effects of these peptides on cytosolic calcium concentration ([Ca2+]c), mitochondrial metabolism, enzyme secretion and cell fate in murine isolated pancreatic acinar cells using fluorescence confocal microscopy and patch-clamp electrophysiology. CCK-58 (1-10pM) induced transient, oscillatory increases of [Ca2+]c, which showed apical to basolateral progression and were associated with a rise of mitochondrial NAD(P)H. CCK-58 (10pM) induced zymogen exocytosis in isolated cells and amylase secretion from isolated cells and whole tissues. Hyperstimulation with supraphysiological CCK-58 (5nM) induced a single large increase of [Ca2+]c that declined to a plateau which remained above the basal level 20 minutes after application and which was dependent on external Ca2+ entry. In cells dispersed from the same tissues, CCK-8 induced similar patterns of responses to those of CCK-58, with oscillatory increases of [Ca2+]c at lower (pM) concentrations and sustained responses at 5nM. CCK-58 and CCK-8 exhibited similar profiles of action on cell death, with increases in necrosis at high CCK-58 and CCK-8 (10nM) that were not significantly different between peptides. The present experiments indicate that CCK-8 and CCK-58 have essentially identical actions on the acinar cell at high and low agonist concentrations, suggesting an action via the same receptor and that the differences observed in an intact rat model may result from indirect effects of the peptides. Our data strengthen the argument that CCK-58 is an important physiological form of this gastrointestinal hormone.

cholecystokinin-58; pancreatic acinar; calcium; mitochondria


* University of Liverpool criddle{at}liv.ac.uk






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