Multiple domains in the C-terminus of NMDA receptor GluN2B subunit contribute to neuronal death following in vitro ischemia

Vieira, Marta; Schmidt, Jeannette; Ferreira, Joana S.; She, Kevin; Oku, Shinichiro; Mele, Miranda; Santos, Ana Lúcia; Duarte, Carlos B.; Craig, Ann Marie; Carvalho, Ana Luı́sa

doi:10.1016/j.nbd.2015.11.007

Cited by 35 publications

(23 citation statements)

References 65 publications

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“…Given the differences in the amino acid sequence of the CTD of each GluN2 subtype, it has been proposed that this domain may additionally provide functional diversity by determining the receptor interactors and downstream effectors of NMDAR activation (Ryan et al, 2008;Vieira et al, 2015;Wyllie et al, 2013). The key role of GluN2 CTD in the responses to NMDAR activation was made clear in studies with chimeric GluN2A subunits expressing the GluN2B CTD.…”

Section: Role Of Nmda Receptors In Excitotoxic Injurymentioning

confidence: 99%

“…The toxic effects observed upon expression of the chimeric receptor subunit were mediated by the recruitment of neuronal nitric oxide synthase (nNOS) to the NMDAR via PSD95, a mechanism dependent on the GluN2B CTD (Aarts et al, 2002). Therefore, disruption of the interactions between GluN2B CTD, PSD95 and signaling proteins through the use of small interfering peptides (GluN2B CTD-PSD95 or PSD95-nNOS) is one of the most promising approaches to reduce ischemic damage, not only in rodents but also in humans (Aarts et al, 2002;Hill et al, 2012;Srejic et al, 2013;Vieira et al, 2015;Zhou et al, 2010).…”

Section: Role Of Nmda Receptors In Excitotoxic Injurymentioning

confidence: 99%

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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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Section: Role Of Nmda Receptors In Excitotoxic Injurymentioning

confidence: 99%

Section: Role Of Nmda Receptors In Excitotoxic Injurymentioning

confidence: 99%

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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“…mCherry-GluN2B (pcDNA3, CMV promotor, modified from SEP-GluN2B (Dupuis et al, 2014) was used as a FRET-negative control. FRET-FLIM experiments were performed 4 days after calcium phosphate precipitation method (Vieira et al, 2016). Briefly, 0.5 µg to 1.5 µg of DNA (per 18 mm coverslips) was mixed with TE (1 mM Tris–HCl pH 7.3, 1 mM EDTA), CaCl 2 (2.5 M CaCl 2 in 10 mM HEPES, pH 7.2) and 2× HEBS (12 mM dextrose, 50 mM HEPES, 10 mM KCl, 280 mM NaCl and 1.5 mM Na 2 HPO 4 ·2H 2 O, pH 7.2).…”

Section: Methodsmentioning

confidence: 99%

Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses

Ferreira

Papouin

Ladépêche

et al. 2017

eLife

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The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single-molecule imaging, biochemistry and electrophysiology, we show that glycine and D-serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes. Acute manipulations of co-agonist levels, both ex vivo and in vitro, unveil that D-serine alter the membrane dynamics and content of GluN2B-NMDAR, but not GluN2A-NMDAR, at synapses through a process requiring PDZ binding scaffold partners. In addition, using FRET-based FLIM approach, we demonstrate that D-serine rapidly induces a conformational change of the GluN1 subunit intracellular C-terminus domain. Together our data fuels the view that the extracellular microenvironment regulates synaptic NMDAR signaling.DOI: http://dx.doi.org/10.7554/eLife.25492.001

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“…As a downstream protein for GluN2B, 37) p-CaMKII is one of the most abundant kinases in the brain and is mainly found in the hippocampus, which is not only an indicator of ischemic brain damage, but also a key enzyme in the excitatory calcium signaling pathway. 38) Therefore, down-regulating the content of p-CaMKII and GluN2B is important for the protection of cerebral I/R injury. In line with that, our result demonstrated that YQTL effectively inhibited the activation of GluN2B and p-CaMKII induced by I/R, highlighting its neuronal protective effects via direct modulation of the GluN2B and p-CaMKII expression ( Fig.…”

Section: Discussionmentioning

confidence: 99%

YiQi Tongluo Granule against Cerebral Ischemia/Reperfusion Injury in Rats by Freezing GluN2B and CaMK II through NMDAR/ERK1/2 Signaling

Li²,

Wang

et al. 2019

Chem. Pharm. Bull.

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Yiqi Tongluo Granule (YQTL) is a kind of proprietary Chinese medicine, manufactured by ChinaShineway Pharmaceutical Group Ltd., under the authority of China Food and Drug Administration (CFDA) treating cardiovascular and cerebrovascular diseases such as ischemic stroke in China, however the underlying mechanism of YQTL on treating ischemic stroke has not been revealed. This study is aimed to evaluate the protective effect of YQTL on cerebral ischemia/reperfusion (I/R) injury and inquire into its underlying mechanisms. Cerebral I/R injury was induced by occluding the middle cerebral artery for 2 h followed by 24 h reperfusion. And regional cerebral flow was monitored by Laser Doppler flow during ischemia phase. The infarct volume was evaluated by Triphenyte-trazolium chloride staining. The protective effects of YQTL were assessed by a number of parameters, including neurological scores, regional cerebral blood flow, pathological changes of neuron in hippocampuses and hippocampus calcium level. The proteins of extracellular signal-regulated kinase (ERK), N-methyl D-aspartate receptor subtype 2B (GluN2B) and p-calcium-dependent protein kinaseII (CaMKII) response were assayed by Western blotting. I/R caused significant change in neurological deficit scores, regional cerebral flow and infarct volume. However results in YQTL groups and Nimodipine Tablets (NMDP) group were reversed. Subsequently YQTL reduced I/R-induced calcium influx. Results of hematoxylin-eosin staining manifested that YQTL significantly improved neuronal injury after I/R in rats. Meanwhile, microdialysis data demonstrated that extracellular glutamate was increased in the striatum during ischemia reperfusion, which was reduced by YQTL. YQTL and mitogen-activated protein extracellular kinase (MEK) inhibitor suppressed the I/R-mediated over-expression of GluN2B, p-ERK, ERK and p-CaMKII proteins expression. Putting these together, our results suggest that YQTL played a neuroprotective role in cerebral I/R injury, which might be exerted by inhibiting the excitotoxicity and expression of GluN2B, p-CaMKII and MEK/ERK signal pathway.

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Multiple domains in the C-terminus of NMDA receptor GluN2B subunit contribute to neuronal death following in vitro ischemia

Cited by 35 publications

References 65 publications

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

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

Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses

YiQi Tongluo Granule against Cerebral Ischemia/Reperfusion Injury in Rats by Freezing GluN2B and CaMK II through NMDAR/ERK1/2 Signaling

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