RyR2 and Calpain-10 Delineate a Novel Apoptosis Pathway in Pancreatic Islets

James D. Johnson, Zhiqiang Han, Kenichi Otani, Honggang Ye, Yan Zhang, Hong Wu, Yukio Horikawa, Stanley Misler, Graeme I. Bell, Kenneth S. Polonsky
2004 Journal of Biological Chemistry  
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
more » ... 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.
doi:10.1074/jbc.m401216200 pmid:15044459 fatcat:57azdkzldfh3ra4geq5ldtus7e