title: Extracellular ATP protects pancreatic duct epithelial cells from alcohol-induced damage through P2Y1 receptor-cAMP signal pathway.
abstract: Extracellular adenosine-5'-triphosphate (ATP) regulates cell death and survival of neighboring cells. The detailed effects are diverse depending on cell types and extracellular ATP concentration. We addressed the effect of ATP on ethanol-induced cytotoxicity in epithelial cells, the cell type that experiences the highest concentrations of alcohol. Using pancreatic duct epithelial cells (PDEC), we found that a micromolar range of ATP reverses all intracellular toxicity mechanisms triggered by exceptionally high doses of ethanol and, thus, improves cell viability dramatically. Out of the many purinergic receptors expressed in PDEC, the P2Y1 receptor was identified to mediate the protective effect, based on pharmacological and siRNA assays. Activation of P2Y1 receptors increased intracellular cyclic adenosine monophosphate (cAMP). The protective effect of ATP was mimicked by forskolin and 8-Br-cAMP but inhibited by a protein kinase A (PKA) inhibitor, H-89. Finally, ATP reverted leakiness of PDEC monolayers induced by ethanol and helped to maintain epithelial integrity. We suggest that purinergic receptors reduce extreme alcohol-induced cell damage via the cAMP signal pathway in PDEC and some other types of cells.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Health Sciences Bldg. Rm. G-424, Seattle, WA, 98195-7290, USA.|Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, 92093, USA.
authors.forename: Jong Bae
authors.initials: JB
authors.lastname: Seo
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Health Sciences Bldg. Rm. G-424, Seattle, WA, 98195-7290, USA.
authors.forename: Seung-Ryoung
authors.initials: SR
authors.lastname: Jung
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Health Sciences Bldg. Rm. G-424, Seattle, WA, 98195-7290, USA.
authors.forename: Bertil
authors.initials: B
authors.lastname: Hille
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Health Sciences Bldg. Rm. G-424, Seattle, WA, 98195-7290, USA. koh@uw.edu.
authors.forename: Duk-Su
authors.initials: DS
authors.lastname: Koh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020011:Protective Agents; D017382:Reactive Oxygen Species; D058472:Receptors, Purinergic P2Y1; D000431:Ethanol; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D002118:Calcium
keywords: ATP; Alcohol; Apoptosis; Pancreatic duct epithelial cells; Purinergic receptor; cAMP