The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress

被引：0

作者：

N Henke

P Albrecht

I Bouchachia

M Ryazantseva

K Knoll

J Lewerenz

E Kaznacheyeva

P Maher

A Methner

机构：

[1] Heinrich-Heine Universität Düsseldorf,Department of Neurology

[2] Institute of Cytology St. Petersburg,Department of Neurology

[3] University of Ulm,Department of Neurology

[4] Cellular Neurobiology Laboratory,undefined

[5] Salk Institute for Biological Studies,undefined

[6] Focus Program Translational Neuroscience (FTN),undefined

[7] Rhine Main Neuroscience Network (rmn2),undefined

[8] Johannes Gutenberg University Medical Center Mainz,undefined

来源：

Cell Death & Disease | 2013年 / 4卷

关键词：

STIM1; SOCE; oxidative stress;

D O I：

暂无

中图分类号：

学科分类号：

摘要：

The mouse hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Addition of extracellular glutamate depletes the cells of glutathione (GSH) by blocking the glutamate−cystine antiporter system xc−. GSH is the main antioxidant in neurons and its depletion induces a well-defined program of cell death called oxytosis, which is probably synonymous with the iron-dependent form of non-apoptotic cell death termed ferroptosis. Oxytosis is characterized by an increase of reactive oxygen species and a strong calcium influx preceding cell death. We found a significant reduction in store-operated calcium entry (SOCE) in glutamate-resistant HT22 cells caused by downregulation of the Ca2+ channel ORAI1, but not the Ca2+ sensors STIM1 or STIM2. Pharmacological inhibition of SOCE mimicked this protection similarly to knockdown of ORAI1 by small interfering RNAs. Long-term calcium live-cell imaging after induction of the cell death program showed a specific reduction in Ca2+-positive cells by ORAI1 knockdown. These results suggest that dysregulated Ca2+ entry through ORAI1 mediates the detrimental Ca2+ entry in programmed cell death induced by GSH depletion. As this detrimental Ca2+ influx occurs late in the course of the cell death program, it might be amenable to therapeutic intervention in diseases caused by oxidative stress.

引用

页码：e470 / e470

共 131 条

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