title: Raf-1 kinase inhibitory protein (RKIP) mediates ethanol-induced sensitization of secretagogue signaling in pancreatic acinar cells.
abstract: Excessive alcohol consumption is associated with most cases of chronic pancreatitis, a progressive necrotizing inflammatory disease that can result in pancreatic insufficiency due to acinar atrophy and fibrosis and an increased risk of pancreatic cancer. At a cellular level acute alcohol exposure can sensitize pancreatic acinar cells to secretagogue stimulation, resulting in dysregulation of intracellular Ca(2+) homeostasis and premature digestive enzyme activation; however, the molecular mechanisms by which ethanol exerts these toxic effects have remained undefined. In this study we identify Raf-1 kinase inhibitory protein as an essential mediator of ethanol-induced sensitization of cholecystokinin- and carbachol-regulated Ca(2+) signaling in pancreatic acinar cells. We show that exposure of rodent acinar cells to ethanol induces protein kinase C-dependent Raf-1 kinase inhibitory protein phosphorylation, sensitization of cholecystokinin-stimulated Ca(2+) signaling, and potentiation of both basal and cholecystokinin-stimulated extracellular signal-regulated kinase activation. Furthermore, we show that either suppression of Raf-1 kinase inhibitory protein expression using short hairpin RNA or gene ablation prevented the sensitizing effects of ethanol on cholecystokinin- and carbachol-stimulated Ca(2+) signaling and intracellular chymotrypsin activation in pancreatic acinar cells, suggesting that the modulation of Raf-1 inhibitory protein expression may have future therapeutic utility in the prevention or treatment of alcohol-associated pancreatitis.
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77555-0722, USA.
authors.forename: Sung Ok
authors.initials: SO
authors.lastname: Kim
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Ives
authors.forename: Xiaofu
authors.initials: X
authors.lastname: Wang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Davey
authors.forename: Celia
authors.initials: C
authors.lastname: Chao
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellmich
mesh_terms: D061354:Acinar Cells / Q000166:cytology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002918:Chymotrypsin / Q000737:chemistry; D000431:Ethanol / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D051379:Mice; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000517:prevention & control; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012306:Risk; D015398:Signal Transduction
chemical_list: D002492:Central Nervous System Depressants; C550693:PEBP1 protein, rat; D049488:Phosphatidylethanolamine Binding Protein; C539308:Raf kinase inhibitory protein, mouse; D043562:Receptors, G-Protein-Coupled; D000431:Ethanol; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D002918:Chymotrypsin; D002118:Calcium