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...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 40; pp. 14386 - 14391 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
04.10.2005
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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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. |
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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 |