title: Calcineurin mediates pancreatic growth in protease inhibitor-treated mice.
abstract: CCK acts on pancreatic acinar cells to increase intracellular Ca(2+) leading to secretion of digestive enzymes and, in the long term, pancreatic growth. Calcineurin (CN) is a serine/threonine-specific protein phosphatase activated by Ca(2+) and calmodulin that 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 powdered 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, whereas levels of MAPKs, ERKs, and p38 were not altered. In summary, 1) CCK released by chronic camostat feeding induces pancreatic growth in mice; 2) this growth is blocked by treatment with both CsA and FK506, indicating a role for CN; 3) CCK stimulation also increases CN protein. In conclusion, activation and possibly upregulation of CN may participate in regulation of pancreatic growth by CCK in mice.
authors.affiliation: Molecular and Integrative Physiology, Univ. of Michigan Medical School, 7744 Medical Science II, Ann Arbor, MI 48109-0622, USA.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Tashiro
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
authors.forename: Rodger A
authors.initials: RA
authors.lastname: Liddle
authors.forename: John A
authors.initials: JA
authors.lastname: Williams
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D002766:Cholecystokinin / Q000378:metabolism / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006146:Guanidines; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010179:Pancreas / Q000187:drug effects* / Q000254:growth & development*; D011480:Protease Inhibitors / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D004952:Esters; D006146:Guanidines; D011480:Protease Inhibitors; C034532:camostat; D016670:Gabexate; D016572:Cyclosporine; D002766:Cholecystokinin; D019703:Calcineurin; D016559:Tacrolimus