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Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14386-91. Epub 2005 Sep 26.

The ryanodine receptor mediates early zymogen activation in pancreatitis.

Author information

1
Department of Pediatrics, Yale University School of Medicine and Veterans Affairs Connecticut Health Care, New Haven, CT 06520, USA. sohail.husain@yale.edu

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.

PMID:
16186498
PMCID:
PMC1242288
DOI:
10.1073/pnas.0503215102
[Indexed for MEDLINE]
Free PMC Article

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