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 Ca2+from undefined intracellular stores. We hypothesized that zymogen activation is mediated by ryanodine receptor (RYR)-regulated Ca2+release, becaus...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 40; pp. 14386 - 14391
Main Authors Husain, Sohail Z., Prasad, Priyajit, Grant, Wayne M., Kolodecik, Thomas R., Nathanson, Michael H., Gorelick, Fred S., Greengard, Paul
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 04.10.2005
National Acad Sciences
Subjects
Acinar cells
Agonists
Animals
Antibodies
Biological Sciences
Calcium
Calcium - metabolism
Cells
Ceruletide - pharmacology
Dantrolene
Dyes
Enzyme Precursors
Enzymes
Male
Medical disorders
Microscopy, Confocal
Models, Biological
Pancreas
Pancreas, Exocrine - cytology
Pancreas, Exocrine - pathology
Pancreatitis
Pancreatitis - metabolism
Pancreatitis - pathology
Pathology
Rats
Rats, Sprague-Dawley
Receptors
Ryanodine Receptor Calcium Release Channel - metabolism
Secretion
Secretory Vesicles - drug effects
Secretory Vesicles - metabolism
Trypsinogen
Zymogens
Online AccessGet full text

Cover

More Information
Summary:Acute pancreatitis is characterized by the pathologic activation of zymogens within pancreatic acinar cells. The process requires a rise in cytosolic Ca2+from undefined intracellular stores. We hypothesized that zymogen activation is mediated by ryanodine receptor (RYR)-regulated Ca2+release, because early zymogen activation takes place in a supranuclear compartment that overlaps in distribution with the RYR. Ca2+signals in the basolateral, but not apical, region of acinar cells observed during supraphysiologic agonist stimulation were dependent on RYR Ca2+release. Inhibition of RYR or depletion of RYR-sensitive Ca2+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 Ca2+release from the RYR mediates zymogen activation but not enzyme secretion. The findings imply a role for the RYR in acute pancreatitis.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 23
This paper was submitted directly (Track II) to the PNAS office.
Edited by Paul Greengard, The Rockefeller University, New York, NY, and approved August 23, 2005
Author contributions: S.Z.H., M.H.N., and F.S.G. designed research; S.Z.H., P.P., W.M.G., and T.R.K. performed research; S.Z.H., P.P., W.M.G., T.R.K., M.H.N., and F.S.G. analyzed data; and S.Z.H., W.M.G., M.H.N., and F.S.G. wrote the paper.
To whom correspondence should be addressed at: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, FMP408, P.O. Box 208064, New Haven, CT 06520. E-mail: sohail.husain@yale.edu.
Abbreviations: (Ca2+)i, cytosolic Ca2+; RYR, ryanodine receptor; IP3R, inositol 1,4,5-trisphosphate receptor; CCK, cholecystokinin; TAP, trypsinogen activation peptide; VIP, vasointestinal polypeptide.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0503215102