Glutamate levels control HT22 murine hippocampal cell death by regulating biphasic patterns of Erk1/2 activation: role of metabolic glutamate receptor 5

Abstract

Extracellular glutamate concentration is a critical determinant of neuronal cell fate. We recently demonstrated that HT22 murine hippocampal cell viability was reduced by exposure to high concentrations of glutamate, whereas low concentrations promoted cell survival. Extracellular signal-regulated kinase (Erk)1/2 activation by glutamate is important for both glutamate-induced cell death and survival. In this study, we investigated the role of glutamate-induced or hydrogen peroxide (H₂O₂)-induced Erk1/2 activation in HT22 cell fate determination. Glutamate and H₂O₂ treatment similarly induced early (<1 h) Erk1/2 phosphorylation regardless of concentration. On the other hand, persistent Erk1/2 phosphorylation (16–24 h) was observed only in the presence of excess glutamate. Only the latter contributed to glutamate-induced cell death, which involved metabolic glutamate receptor 5. Our findings suggest that glutamate concentration modulates two distinct phases of Erk1/2 activation, which can explain the glutamate concentration-dependent determination of HT22 cell fate.

Graphical abstract

Glutamate concentration modulates two distinct phases of Erk1/2 activation, which can explain the glutamate concentration-dependent determination of HT22 cell fate.

Key words:

• glutamate
• HT22 cells
• Erk1/2
• mGluR1
• mGluR5

Acknowledgments

The authors thank Dr. Gabriel Livera (Université Paris Diderot Paris 7, France), Dr. Céline Méhats (Institut Cochin, France), and Dr. Masugi Nishihara (The University of Tokyo, Japan) for many helpful comments.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes

Abbreviations: AIDA, 1-aminoindan-1,5-dicarboxylic acid; DMEM, Dulbecco’s modified Eagle’s medium; Erk, extracellular signal-regulated kinase; mGluR, metabolic glutamate receptors; MPEP, 2-methyl-6-(phenylethynyl)pyridine; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide; NGF, nerve growth factor; NMDA, N-methyl-d-aspartate; PI3 K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; SDS, sodium dodecyl sulfate.