Glutamate Activates Protein Kinase B (PKB/Akt) through AMPA Receptors in Cultured Bergmann Glia Cells

Morales, M. M.; González-Mejia, M. Elba; Bernabé, A.; Hernández‐Kelly, Luisa C.; Ortega, Arturo

doi:10.1007/s11064-005-9034-2

Cited by 11 publications

(8 citation statements)

References 23 publications

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“…We have previously reported that nicotinic acetylcholine receptor stimulation also protects neurons against glutamate through the PI3K‐Akt system (Kihara et al, 2001). Stimulation of AMPA receptors activates the PI3K‐Akt system via Src (Morales et al, 2006). It has been reported that AMPA protects neurons against glutamate excitotoxicity through PI3K activation (Wu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate attenuates glutamate‐induced caspase‐3 cleavage via regulation of glycogen synthase kinase 3β

Nishimoto

Kihara

Akaike

et al. 2007

J of Neuroscience Research

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Preconditioning of sublethal ischemia exhibits neuroprotection against subsequent ischemia-induced neuronal death. It has been indicated that glutamate, an excitatory amino acid, is involved in the pathogenesis of ischemia-induced neuronal death or neurodegeneration. To elucidate whether prestimulation of glutamate receptor could counter ischemia-induced neuronal death or neurodegeneration, we examined the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), an ionotropic subtype of glutamate receptor, on excess glutamate-induced excitotoxicity using primary cortical neuronal cultures. We found that AMPA exerted a neuroprotective effect in a time- and concentration-dependent manner. A blocker of phosphatidylinositol-3 kinase (PI3K), LY294002 (10 microM), significantly attenuated AMPA-induced protection. In addition, Ser473 of Akt/PKB, a downstream target of PI3K, was phosphorylated by AMPA administration (10 microM). Glycogen synthase kinase 3beta (GSK3beta), which has been reported to be inactivated by Akt, was phosphorylated at Ser9 by AMPA. Ser9-phosphorylated GSK3beta or inactivated form would be a key molecule for neuroprotection, insofar as lithium chloride (100 microM) and SB216763 (10 microM), inhibitors of GSK3beta, also induced phosphorylation of GSK3beta at Ser9 and exerted neuroprotection, respectively. Glutamate (100 microM) increased cleaved caspase-3, an apoptosis-related cysteine protease, and caspase-3 inhibitor (Ac-DEVD-CHO; 1 microM) blocked glutamate-induced excitotoxicity in our culture. AMPA (10 microM, 24 hr) and SB216763 (10 microM) prominently decreased glutamate-induced caspase-3 cleavage. These findings suggest that AMPA activates PI3K-Akt and subsequently inhibits GSK3beta and that inactivated GSK3beta attenuates glutamate-induced caspase-3 cleavage and neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate attenuates glutamate‐induced caspase‐3 cleavage via regulation of glycogen synthase kinase 3β

Nishimoto

Kihara

Akaike

et al. 2007

J of Neuroscience Research

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“…[53–5593] Several key processes seem to be involved and include PTEN, NF-κB, Akt, and calpain2, all of which are linked to glutamate receptors, either directly or indirectly. [45355848590]…”

Section: Glutamate-induced Cell Signaling and Glioma Invasionmentioning

confidence: 99%

“…[46] Akt expression is linked to NF-κB activation, which is in turn activated by glutamate. [5684] The latter observation provides a link between inflammation, glutamate receptor activation (immunoexcitotoxicity), and tumor invasion and aggressiveness.…”

Section: Glutamate-induced Cell Signaling and Glioma Invasionmentioning

confidence: 99%

Immunoexcitatory mechanisms in glioma proliferation, invasion and occasional metastasis

Blaylock

2013

Surg Neurol Int

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There is increasing evidence of an interaction between inflammatory cytokines and glutamate receptors among a number of neurological diseases including traumatic brain injuries, neurodegenerative diseases and central nervous system (CNS) infections. A number of recent studies have now suggested a strong relation between inflammatory mechanisms and excitatory cascades and these may play a role in glioma invasiveness and proliferation.Chronic inflammation appears to be a major initiating mechanism in most human cancers, involving cell-signaling pathways, which are responsible for cell cycling, cancer cell migration, invasion, tumor aggressiveness, and angiogenesis. It is less well appreciated that glutamate receptors also play a significant role in both proliferation and especially glioma invasion. There is some evidence that sustained elevations in glutamate may play a role in initiating certain cancers and new studies demonstrate an interaction between inflammation and glutamate receptors that may enhance tumor invasion and metastasis by affecting a number of cell-signaling mechanisms. These mechanisms are discussed in this paper as well as novel treatment options for reducing immune-glutamate promotion of cancer growth and invasion.

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“…Glutamate has been shown to activate AKT through the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor in glial cells 62 and glioblastoma cells, 63 a process that may lead to invasive growth and anaplasia in tumor cells. In addition to AMPA receptor involvement, N-methyl-D-aspartic acid (NMDA) receptor stimulation leads to AKT activation in a PI3K-dependent manner, 64 and this activation results in cell death which is necrotic in nature.…”

Section: Phosphatase and Tensin Homolog (Pten) And Aktmentioning

confidence: 99%

Molecular mechanisms of necrosis in glioblastoma: The role of glutamate excitotoxicity

Noch

Khalili²

2009

Cancer Biology & Therapy

125

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Glioblastomas continue to rank among the most lethal primary human tumors. Despite treatment with the most rigorous surgical interventions along with the most optimal chemotherapeutic and radiation regimens, the median survival is just 12–15 months for patients with glioblastoma. Among the histological hallmarks of glioblastoma, necrosis has been demonstrated to be a powerful predictor of poor patient prognosis. Over the years, there have been many advances in our understanding of the molecular mechanisms underlying glioblastoma formation, yet the mechanisms that lead to tumor necrosis remain unclear. One pathway that may lead to necrosis in glioblastoma involves the neurotransmitter, glutamate, which has been shown to accumulate in the peritumoral fluid as a result of decreased cellular uptake by glioblastoma cells. This accumulation leads to subsequent glutamate excitotoxicity and probable necrosis through a massive elevation of intracellular Ca2+ and reduction in cellular ATP levels. We propose that a pathway involving tumor necrosis factor-α (TNF-α), astrocyte-elevated gene-1 (AEG-1), and nuclear factor-kappa B (NF-κB) leads to decreased glutamate uptake through coordinated downregulation of the excitatory amino acid transporter 2 (EAAT2), the glutamate transporter responsible for the majority of glutamate uptake in the human brain. In addition, we suggest that AEG-1 signaling, loss of phosphatase and tensin homolog (PTEN), and ionotropic glutamate receptor activity lead to AKT pathway activation, which results in nutrient overconsumption and necrosis. Together, these pathways provide a new perspective on glioblastoma necrosis involving the process of glutamate excitotoxicity. Future research should address the components of these molecular pathways in order to better understand the mechanism of necrosis in glioblastoma and to begin to develop targeted therapies that may improve patient prognosis in the future.

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Glutamate Activates Protein Kinase B (PKB/Akt) through AMPA Receptors in Cultured Bergmann Glia Cells

Cited by 11 publications

References 23 publications

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate attenuates glutamate‐induced caspase‐3 cleavage via regulation of glycogen synthase kinase 3β

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate attenuates glutamate‐induced caspase‐3 cleavage via regulation of glycogen synthase kinase 3β

Immunoexcitatory mechanisms in glioma proliferation, invasion and occasional metastasis

Molecular mechanisms of necrosis in glioblastoma: The role of glutamate excitotoxicity

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