The ryanodine receptor mediates early zymogen activation in pancreatitis.
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.
Husain
Sohail Z
SZ
Department of Pediatrics, Yale University School of Medicine and Veterans Affairs Connecticut Health Care, New Haven, CT 06520, USA. sohail.husain@yale.edu
Prasad
Priyajit
P
Grant
Wayne M
WM
Kolodecik
Thomas R
TR
Nathanson
Michael H
MH
Gorelick
Fred S
FS
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
D004792:Enzyme Precursors; D019837:Ryanodine Receptor Calcium Release Channel; D002108:Ceruletide; D014362:Trypsinogen; D003620:Dantrolene; D002118:Calcium