title: Calcium efflux from the endoplasmic reticulum leads to β-cell death.
abstract: It has been established that intracellular calcium homeostasis is critical for survival and function of pancreatic β-cells. However, the role of endoplasmic reticulum (ER) calcium homeostasis in β-cell survival and death is not clear. Here we show that ER calcium depletion plays a critical role in β-cell death. Various pathological conditions associated with β-cell death, including ER stress, oxidative stress, palmitate, and chronic high glucose, decreased ER calcium levels and sarcoendoplasmic reticulum Ca(2+)-ATPase 2b expression, leading to β-cell death. Ectopic expression of mutant insulin and genetic ablation of WFS1, a causative gene for Wolfram syndrome, also decreased ER calcium levels and induced β-cell death. Hyperactivation of calpain-2, a calcium-dependent proapoptotic protease, was detected in β-cells undergoing ER calcium depletion. Ectopic expression of sarcoendoplasmic reticulum Ca(2+)-ATPase 2b, as well as pioglitazone and rapamycin treatment, could prevent calcium efflux from the ER and mitigate β-cell death under various stress conditions. Our results reveal a critical role of ER calcium depletion in β-cell death and indicate that identification of pathways and chemical compounds restoring ER calcium levels will lead to novel therapeutic modalities and pharmacological interventions for type 1 and type 2 diabetes and other ER-related diseases including Wolfram syndrome.
authors.affiliation: Department of Medicine (T.H., J.M., K.K., M.H., S.L., F.U.), Division of Endocrinology, Metabolism, and Lipid Research, and Department of Pathology and Immunology (F.U.), Washington University School of Medicine, St Louis, Missouri 63110; and Cardiovascular-Metabolics Research Laboratories (T.H.), Daiichi Sankyo Co, Ltd, Tokyo 103-8426, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hara
authors.forename: Jana
authors.initials: J
authors.lastname: Mahadevan
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.forename: Mariko
authors.initials: M
authors.lastname: Hara
authors.forename: Simin
authors.initials: S
authors.lastname: Lu
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D002469:Cell Separation; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008297:Male; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium