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 ␤-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

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... tic 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 ␤-cell survival in vitro by suppressing a death pathway mediated by calpain-10, a type 2 diabetes susceptibility gene with previously unknown function. . 1 The abbreviations used are: ER, endoplasmic reticulum; IP 3 , inositol trisphosphate; RyR, ryanodine receptor; DEVD-CHO, Asp-Glu-Val-Asp/Chinese hamster ovary; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling; ES, embryonic stem; ALLM, N-acetyl-Leu-Leu-Met-CHO; CICR, Ca 2ϩ -induced Ca 2ϩ release.