Phosphorylation of NMDA 2B at S1303 in human glioma peritumoral tissue: implications for glioma epileptogenesis

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>Peritumoral seizures are an early symptom of a glioma. To gain a better understanding of the molecular mechanism underlying tumor-induced epileptogenesis, the authors studied modulation of the <jats:italic>N</jats:italic>-methyl-<jats:sc>d</jats:sc>-aspartate (NMDA) receptor in peritumoral tissue.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>To study the possible etiology of peritumoral seizures, NMDA receptor expression, posttranslational modification, and function were analyzed in an orthotopic mouse model of human gliomas and primary patient glioma tissue in which the peritumoral border (tumor-brain interface) was preserved in a tissue block during surgery.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>The authors found that the NMDA receptor containing the 2B subunit (NR2B), a predominantly extrasynaptic receptor, is highly phosphorylated at S1013 in the neurons located in the periglioma area of the mouse brain. NR2B is also highly phosphorylated at S1013 in the neurons located in the peritumoral area from human brain tissue containing a glioma. The phosphorylation of the extrasynaptic NMDA receptor increases its permeability for Ca<jats:sup>2+</jats:sup> influx and subsequently mediates neuronal overexcitation and seizure activity.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These data suggest that overexcitation of the extrasynaptic NMDA receptors in the peritumoral neurons may contribute to the development of peritumoral seizures and that the phosphorylated NR2B may be a therapeutic target for blocking primary brain tumor–induced peritumoral seizures.</jats:p></jats:sec>

Epilepsy Associates with Decreased HIF-1α/STAT5b Signaling in Glioblastoma

“…Others have demonstrated that specific tumor biological effects are associated with epilepsy in glioma patients, such as neuronal excitation/inhibition disbalance and expression changes in the glutamate pathway [10,11,12,13,14,15]. Also, IDH1 mutation was linked to the risk of tumor-associated epilepsy and seizure prognosis [16,17].…”

“…For instance, the release of D-2-hydroxyglutarate (D2HG), a substance structurally similar to glutamate, in the tumor microenvironment was associated with epilepsy [10]. NR2B, a predominantly extrasynaptic NMDA glutamate receptor, is highly phosphorylated in peritumoral mouse brain tissue, and increases Ca 2+ influx in the cells, leading to a self-activating circle and overexcitation of neurons [11,12]. Another proposed mechanism of tumor-associated seizures is mediated by the glutamate release pathway cystine/glutamate transporter System Xc−(SXC), which expression is elevated in a subset of glioblastoma tissues, and in peritumoral tissues.…”

Neuroprotective derivatives of tacrine that target NMDA receptor and acetyl cholinesterase - Design, synthesis and biological evaluation

“…(G) Heatmap of the binding energies (MM-GBSA in kcal/mol) obtained for designed MTDLs after ensemble docking. Ligands that are synthesized in the current studies 19,23,24,(26)(27)(28)(29)31,33,(38)(39)(40)(45)(46)(47)58,61 and 68) are marked.…”

“…In conditions like oxygen-glucose deprivation in brain slices [26] and in NMDA-induced excitotoxicity in cultured neurons [27], the role of NMDAR as a potential target for neuroprotection has already been demonstrated. Variations in NMDAR activity are associated with ischemic conditions [28], stroke [29], traumatic brain injury (TBI) [30], glioma [31] and neuropsychiatric diseases [32,33], suggesting the therapeutic potential of NMDAR modulators in these conditions. The involvement of NMDARs in pain circuitries makes it a potential target for analgesic drugs [34].…”

Transmembrane protein GRINA modulates aerobic glycolysis and promotes tumor progression in gastric cancer

“…Blockade of the NMDA receptor in breast cancer or small cell lung cancer can promote apoptosis of tumour cells, and NMDA receptor is also regarded as a potential therapeutic target in ovarian cancer [10]. In primary encephaloma, NMDA2B phosphorylation can prevent the epileptic seizures caused by tumours [11]. In gastric cancer, knockdown of NR2A, which also belongs to NMDA receptor family, induced cell cycle to arrest in the G1 phase and suppressed the proliferation of MKN45 cells [12].…”