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1 Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA
2 Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI, USA
3 Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI, USA; Department of Medicine, Duke University Medical Center, Durham, NC, USA
* To whom correspondence should be addressed. E-mail: jawillms{at}umich.edu.
Cholecystokinin (CCK) acts on pancreatic acinar cells to increase intracellular Ca2+ leading to secretion of digestive enzymes and, in the long term, pancreatic growth. Calcineurin (CN) is a serine/threonine-specific protein phosphatase that is activated by Ca2+ and calmodulin and recently has been shown to participate in the growth regulation of cardiac and skeletal myocytes. We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release. Mice were fed a powder diet with or without 0.1% camostat. Pancreatic wet weight, protein and DNA were increased in response to camostat in a time-dependent manner over 10 days in ICR mice but not in CCK-deficient mice. Both CsA (15 mg/kg) and FK506 (3 mg/kg) given twice daily blocked the increase in pancreatic wet weight, and protein and DNA content induced by camostat. The increase in plasma CCK induced by camostat was not blocked by CsA or FK506. Camostat feeding also increased the relative amount of CN protein, while levels of mitogen-activated protein kinases ERKs and p38 were not altered. In summary, (i) CCK released by chronic camostat feeding induces pancreatic growth in mice; (ii) this growth is blocked by treatment with both CsA and FK506 indicating a role for CN; (iii) CCK stimulation also increases CN protein. In conclusion, activation and possibly up-regulation of CN may participate in regulation of pancreatic growth by CCK in mice.
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