Abstract
Receptor-interacting protein 1 (RIP1), a molecular switch protein from apoptosis to necroptosis, is regarded to play an essential role in necroptotic cell death. Although the increased RIP1 activity induced by tumor necrosis factor α activates mitogen-activated protein kinases (MAPKs) including ERK and leads to apoptotic or necrotic cell death, it is unclear what is the role of ERK during the process of necroptosis. In this study, our data demonstrated that ERK inhibitors U0126 and PD98059 blocked glutamate-induced necroptosis in HT-22 cells, indicating the critical role of ERK activation in necroptosis. Further, we found glutamate treatment increased phosphorylated ERK1/2 level, but the specific necroptosis inhibitor Necrostatin-1 (Nec-1) significantly inhibited the phosphorylation of ERK1 (P44) at 5, 10, and 15 min after glutamate treatment; the phosphorylation of ERK2 (P42) level was also markedly reduced by Nec-1 at 10 min after glutamate treatment. The phosphorylation of JNK and P38, two other MAPK members, were slightly increased after glutamate treatment, but Nec-1 had no inhibitory effect on JNK and P38 activation. Our finding suggested that ERK activation may play an important role in necroptotic cell death and the inhibition of ERK activation mediated the protection of Nec-1 on glutamate-induced necroptosis. Since ERK is considered as a downstream of RIP1, the RIP1/ERK signal pathway may provide new therapeutic avenues for the treatment of ischemia–reperfusion damage and neurodegenerative diseases-containing necroptotic cell death.
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Abbreviations
- BFA:
-
Bafilomycin A1
- ERK:
-
Extracellular signal-regulated kinase
- JNK:
-
c-Jun N-terminal kinase
- MTS:
-
3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2(4-sulfophenyl)2-H-tetrazolium, inner salt
- MAPK:
-
Mitogen-activated protein kinase
- RIP1:
-
Receptor-interacting protein 1
- Nec-1:
-
Necrostatin-1
- Nec-1i:
-
Inactive form of Nec-1
- TNFα:
-
Tumor necrosis factor α
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Acknowledgments
This study was supported by the Grant 30700245 from the National Natural Science Foundation of China and the SBK201221577 from Jiangsu province Natural Science Foundation.
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Min Zhang and Jizhen Li contributed equally to this study.
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Zhang, M., Li, J., Geng, R. et al. The Inhibition of ERK Activation Mediates the Protection of Necrostatin-1 on Glutamate Toxicity in HT-22 Cells. Neurotox Res 24, 64–70 (2013). https://doi.org/10.1007/s12640-012-9361-4
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DOI: https://doi.org/10.1007/s12640-012-9361-4