title: Low extracellular pH induces damage in the pancreatic acinar cell by enhancing calcium signaling.
abstract: Low extracellular pH (pHe) occurs in a number of clinical conditions and sensitizes to the development of pancreatitis. The mechanisms responsible for this sensitization are unknown. Because abnormal Ca(2+) signaling underlies many of the early steps in the pathogenesis of pancreatitis, we evaluated the effect of decreasing pHe from 7.4 to 7.0 on Ca(2+) signals in the acinar cell. Low pHe significantly increased the amplitude of cerulein-induced Ca(2+) signals. The enhancement in amplitude was localized to the basolateral region of the acinar cell and was reduced by pretreatment with ryanodine receptor (RYR) inhibitors. Because basolateral RYRs also have been implicated in the pathogenesis of pancreatitis, we evaluated the effects of RYR inhibitors on pancreatitis responses in acidic conditions. RYR inhibitors significantly reduced the sensitizing effects of low pHe on zymogen activation and cellular injury. These findings suggest that enhanced RYR-mediated Ca(2+) signaling in the basolateral region of the acinar cell is responsible for the injurious effects of low pHe on the exocrine pancreas.
authors.affiliation: Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut 06515, USA. amc78@omega.med.yale.edu
authors.forename: Anamika M
authors.initials: AM
authors.lastname: Reed
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
authors.forename: Edwin
authors.initials: E
authors.lastname: Thrower
authors.forename: Martine
authors.initials: M
authors.lastname: Alexandre
authors.forename: Ahsan
authors.initials: A
authors.lastname: Shah
authors.forename: Fred S
authors.initials: FS
authors.lastname: Gorelick
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nathanson
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020013:Calcium Signaling; D002478:Cells, Cultured; D006863:Hydrogen-Ion Concentration; D046790:Pancreas, Exocrine / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel