The ryanodine receptor mediates early zymogen activation in pancreatitis

doi:10.1073/pnas.0503215102

The ryanodine receptor mediates early zymogen activation in pancreatitis

Departments of ^*Pediatrics and ^‡Internal Medicine, Yale University School of Medicine and Veterans Affairs Connecticut Health Care, New Haven, CT 06520

Edited by Paul Greengard, The Rockefeller University, New York, NY, and approved August 23, 2005 (received for review April 19, 2005)

Abstract

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.

Footnotes

↵ † 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{at}yale.edu.
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.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: (Ca²⁺)_i, cytosolic Ca²⁺; RYR, ryanodine receptor; IP3R, inositol 1,4,5-trisphosphate receptor; CCK, cholecystokinin; TAP, trypsinogen activation peptide; VIP, vasointestinal polypeptide.