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PMID:15044459
| Citation |
Johnson, JD, Han, Z, Otani, K, Ye, H, Zhang, Y, Wu, H, Horikawa, Y, Misler, S, Bell, GI and Polonsky, KS (2004) RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J. Biol. Chem. 279:24794-802 |
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| 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. |
| Links |
PubMed Online version:10.1074/jbc.M401216200 |
| Keywords |
Animals; Apoptosis; Calcium/metabolism; Calpain/metabolism; Calpain/physiology; Caspase 3; Caspases/metabolism; Cell Survival; Dantrolene/metabolism; Enzyme Activation; Gene Expression Regulation; Glucagon-Like Peptides; Glucose/metabolism; Humans; Islets of Langerhans/metabolism; Islets of Langerhans/pathology; Mice; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Microscopy, Fluorescence; Models, Biological; Palmitic Acids/chemistry; Peptides/pharmacology; Protein Isoforms; RNA, Messenger/metabolism; Ryanodine/metabolism; Ryanodine Receptor Calcium Release Channel/physiology; Time Factors |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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