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J Biol Chem. 2004 Jun 4;279(23):24794-802. Epub 2004 Mar 25.

RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets.

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1
Department of Internal Medicine, Washington University, St. Louis, Missouri 63110, USA.

Abstract

Cells are programmed to die when critical signaling and metabolic pathways are disrupted. Inhibiting the type 2 ryanodine receptor (RyR2) in human and mouse pancreatic beta-cells markedly increased apoptosis. This mode of programmed cell death was not associated with robust caspase-3 activation prompting a search for an alternative mechanism. Increased calpain activity and calpain gene expression suggested a role for a calpain-dependent death pathway. Using a combination of pharmacological and genetic approaches, we demonstrated that the calpain-10 isoform mediated ryanodine-induced apoptosis. Apoptosis induced by the fatty acid palmitate and by low glucose also required calpain-10. Ryanodine-induced calpain activation and apoptosis were reversed by glucagon-like peptide or short-term exposure to high glucose. Thus RyR2 activity seems to play an essential role in beta-cell survival in vitro by suppressing a death pathway mediated by calpain-10, a type 2 diabetes susceptibility gene with previously unknown function.

PMID:
15044459
DOI:
10.1074/jbc.M401216200
[Indexed for MEDLINE]
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