title: The ryanodine receptor mediates early zymogen activation in pancreatitis.
abstract: Acute pancreatitis is characterized by the pathologic activation of zymogens within pancreatic acinar cells. The process requires a rise in cytosolic Ca(2+) from undefined intracellular stores. We hypothesized that zymogen activation is mediated by ryanodine receptor (RYR)-regulated Ca(2+) release, because early zymogen activation takes place in a supranuclear compartment that overlaps in distribution with the RYR. Ca(2+) signals in the basolateral, but not apical, region of acinar cells observed during supraphysiologic agonist stimulation were dependent on RYR Ca(2+) release. Inhibition of RYR or depletion of RYR-sensitive Ca(2+) pools each reduced pathologic zymogen activation in isolated acinar cells, but neither treatment affected amylase secretion. Inhibition of RYR also inhibited zymogen activation in vivo. We propose that Ca(2+) release from the RYR mediates zymogen activation but not enzyme secretion. The findings imply a role for the RYR in acute pancreatitis.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine and Veterans Affairs Connecticut Health Care, New Haven, CT 06520, USA. sohail.husain@yale.edu
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
authors.forename: Priyajit
authors.initials: P
authors.lastname: Prasad
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Grant
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kolodecik
authors.forename: Michael H
authors.initials: MH
authors.lastname: Nathanson
authors.forename: Fred S
authors.initials: FS
authors.lastname: Gorelick
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002108:Ceruletide / Q000494:pharmacology; D003620:Dantrolene; D004792:Enzyme Precursors; D008297:Male; D018613:Microscopy, Confocal; D008954:Models, Biological; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000473:pathology; D010195:Pancreatitis / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism*; D014362:Trypsinogen
chemical_list: D004792:Enzyme Precursors; D019837:Ryanodine Receptor Calcium Release Channel; D002108:Ceruletide; D014362:Trypsinogen; D003620:Dantrolene; D002118:Calcium