Involvement of the GluN2A and GluN2B Subunits in Synaptic and Extrasynaptic N-methyl-d-aspartate Receptor Function and Neuronal Excitotoxicity

Zhou, Xianju; Ding, Qi; Chen, Zhuoyou; Yun, Huifang; Wang, Hongbing

doi:10.1074/jbc.m113.482000

Cited by 119 publications

(104 citation statements)

References 58 publications

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“…Statistically significant differences from controls were determined by Student t test. * P \ 0.05 compared with control Our data also indicate that NMDA glutamate receptors participated in these effects since MK-801, a NMDA noncompetitive antagonist and ifenprodil, a blocker of extra-synaptic NR2B subunit-containing NMDARs (Zhou et al 2013a), totally prevented HMG-induced IF hypophosphorylation. Taking into account that activation of NR2B subunit results in inhibition of cAMP/PKA/ CREB signaling pathway (Corcoran et al 2013), it is proposed that HMG-elicited PKA down-regulation could be, at least partially, ascribed to the NR2B subunit.…”

Section: Discussionsupporting

confidence: 59%

NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease

et al. 2015

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Neurological symptoms and cerebral abnormalities are commonly observed in patients with 3-hydroxy-3-methylglutaryl-CoA lyase (HMG lyase) deficiency, which is biochemically characterized by predominant tissue accumulation of 3-hydroxy-3-methylglutaric (HMG), 3-methylglutaric (MGA), and 3-methylglutaconic (MGT) acids. Since the pathogenesis of this disease is poorly known, the present study evaluated the effects of these compounds on the cytoskeleton phosphorylating system in rat brain. HMG, MGA, and MGT caused hypophosphorylation of glial fibrillary acidic protein (GFAP) and of the neurofilament subunits NFL, NFM, and NFH. HMG-induced hypophosphorylation was mediated by inhibiting the cAMP-dependent protein kinase (PKA) on Ser55 residue of NFL and c-Jun kinase (JNK) by acting on KSP repeats of NFM and NFH subunits. We also evidenced that the subunit NR2B of NMDA receptor and Ca(2+) was involved in HMG-elicited hypophosphorylation of cytoskeletal proteins. Furthermore, the antioxidants L-NAME and TROLOX fully prevented both the hypophosphorylation and the inhibition of PKA and JNK caused by HMG, suggesting that oxidative damage may underlie these effects. These findings indicate that the main metabolites accumulating in HMG lyase deficiency provoke hypophosphorylation of cytoskeleton neural proteins with the involvement of NMDA receptors, Ca(2+), and reactive species. It is presumed that these alterations may contribute to the neuropathology of this disease.

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Section: Discussionsupporting

confidence: 59%

NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease

et al. 2015

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“…Similarly, ifenprodil was more effective than NVP-AAM077, a preferential GluN2A inhibitor, in reducing OGD-induced excitotoxicity as well as NMDAR-mediated elevation of [Ca 2+ ]i in cultured cortical neurons (Zhou et al, 2013a). In addition, the NMDA-induced cell death in hippocampal slices and cultured cerebrocortical neurons was found to be mediated by NMDAR containing GluN2B subunits, and insensitive to antagonists of GluN2A subunits Zhou and Baudry, 2006).…”

Section: Role Of Nmda Receptors In Excitotoxic Injurymentioning

confidence: 88%

“…Thus, the synaptic population of NMDAR was shown to mediate the excitotoxic damage in cultured hippocampal neurons subjected to hypoxic conditions and no protection was observed when extrasynaptic NMDAR were blocked (Wroge et al, 2012). A different set of studies, performed in cultured cortical neurons, showed no preferential coupling of synaptic or extrasynaptic NMDAR to excitotoxic injury (Zhou et al, 2013a). In the latter culture system, activation of synaptic or extrasynaptic NMDAR alone did not cause measurable cell death, but instead stimulated pro-survival signaling mechanisms (CREB, ERK, Akt).…”

Section: Activation Of Synaptic Vs Extrasynaptic Nmdar and Neuronal Dmentioning

confidence: 98%

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

Curcio

Salazar

Mele

et al. 2016

Progress in Neurobiology

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“…IDO activity has been found in human fetal mixed brain cells but without differentiating which cell types express IDO and produce QA [48]. The presence of QA and enzymes involved in the production or metabolism of QA has been demonstrated in normal or pathological brain areas and it was accepted as an endogenous excitotoxin involved in NMDA receptor over activation-associated excitotoxicity [49][50][51]. In addition to production of excitotoxicity through activation of NMDA receptors, previous studies have shown that QA leads to neuroinflammation, and is involved in a variety of neurodegenerative diseases [52][53][54][55].…”

Section: Discussionmentioning

confidence: 99%

Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

et al. 2017

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It has been reported that activation of NF-κB is involved in excitotoxicity; however, it is not fully understood how NF-κB contributes to excitotoxicity. The aim of this study is to investigate if NF-κB contributes to quinolinic acid (QA)-mediated excitotoxicity through activation of microglia. In the cultured primary cortical neurons and microglia BV-2 cells, the effects of QA on cell survival, NF-κB expression and cytokines production were investigated. The effects of BV-2-conditioned medium (BCM) on primary cortical neurons were examined. The effects of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, and minocycline (MC), an inhibitor of microglia activation, on QA-induced excitotoxicity were assessed. QA-induced NF-κB activation and TNF-α secretion, and the roles of TNF-α in excitotoxicity were studied. QA at the concentration below 1 mM had no apparent toxic effects on cultured primary neurons or BV-2 cells. However, addition of QA-primed BCM to primary neurons did aggravate QA-induced excitotoxicity. The exacerbation of QA-induced excitotoxicity by BCM was partially ameliorated by inhibiting NF-κB and microglia activation. QA induced activation of NF-κB and upregulation of TNF-α in BV-2 cells. Addition of recombinant TNF-α mimicked QA-induced excitotoxic effects on neurons, and neutralizing TNF-α with specific antibodies partially abolished exacerbation of QA-induced excitotoxicity by BCM. These studies suggested that QA activated microglia and upregulated TNF-α through NF-κB pathway in microglia. The microglia-mediated inflammatory pathway contributed, at least in part, to QA-induced excitotoxicity.

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Involvement of the GluN2A and GluN2B Subunits in Synaptic and Extrasynaptic N-methyl-d-aspartate Receptor Function and Neuronal Excitotoxicity

Cited by 119 publications

References 58 publications

NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease

NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

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