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.

Neuroprotective effects of an in vitro BBB permeable phenoxythiophene sulfonamide small molecule in glutamate‑induced oxidative injury

“…Moreover, Erk1/2 phosphorylation was markedly reduced following B355227 co-exposure, suggesting an apoptotic role of Erk1/2. Consistent with the results of previous studies, the present study reported that the levels of p-Erk1/2 were increased following glutamate treatment in HT22 cells, leading to cell death (18,49,50). Following treatment with B355227, the phosphorylation of Erk1/2 decreased, leading to an increase in the levels of cell survival.…”

“…ROS plays a central role in glutamate-mediated oxidative stress and displays a synergistic association with Erk1/2 (47). However, in ischemia, Erk1/2 plays key roles in both the survival and apoptosis of cells, depending on the time and concentration of glutamate exposure (48,49). In the present study, an increase in the levels of Erk1/2 phosphorylation was revealed following 24 h glutamate exposure.…”

AMPA receptor expression in mouse testis and spermatogonial GC‐1 cells: A study on its regulation by excitatory amino acids

“…14 Accordingly, numerous studies have shown that Glutamate administration to neuronal and nonneuronal cells induces a rapid increase in ERK1/2 and Akt phosphorylation. [51][52][53][54] It is known that both ERK and Akt pathways regulate multiple biological functions including gene expression and cell cycle 55,56 and that, in the testis, they play a crucial role in spermatogonia proliferation. [57][58][59][60][61] In line with these results, we found an increase of PCNA and Aurora B protein expression in lysated NMDA-and L-Glu-treated GC-1cells.…”

Neuroprotective effects of myristargenol A against glutamate-induced apoptotic HT22 cell death

“…14 The extracellular signal-regulated kinases (ERKs) 1 and 2 (1/2) promote cell growth and differentiation; moreover, oxidative stress induces the sustained phosphorylation of ERKs 1/2. 15 Furthermore, c-Jun N terminal kinase (JNK) and p38 have been shown to modulate cell differentiation and death by cytokines, ultraviolet light, heat shock, and a variety of other factors. 16 Therefore, the identication of antioxidants that can weaken the level of glutamate-induced apoptosis is a good strategy for the prevention and treatment of neurodegenerative diseases.…”