The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults

Martel, Marc-André; Ryan, Tomás J.; Bell, Karen; Fowler, Jill H.; McMahon, Aoife; Al-Mubarak, Bashayer; Komiyama, Noboru H.; Horsburgh, Karen; Kind, Peter C.; Grant, Seth G. N.; Wyllie, David J. A.; Hardingham, Giles E.

doi:10.1016/j.neuron.2012.03.021

Cited by 167 publications

(166 citation statements)

References 72 publications

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“…Synaptic calcium-permeable AMPARs are increased, suggesting a change in APMAR phenotype. The NR2B subunit was found previously to enhance the NMDAR excitotoxicity (22). This explains the neuroprotective effect of miR-223 overexpression and the enhanced vulnerability of the hippocampal CA1 neurons in miR-223 KO mice to excitotoxicity and BCCAO compared with WT mice.…”

Section: Discussionmentioning

confidence: 56%

MicroRNA-223 is neuroprotective by targeting glutamate receptors

Harraz

Eacker²,

Wang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

257

183

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Stroke is a major cause of mortality and morbidity worldwide. Extracellular glutamate accumulation leading to overstimulation of the ionotropic glutamate receptors mediates neuronal injury in stroke and in neurodegenerative disorders. Here we show that miR-223 controls the response to neuronal injury by regulating the functional expression of the glutamate receptor subunits GluR2 and NR2B in brain. Overexpression of miR-223 lowers the levels of GluR2 and NR2B by targeting 3′-UTR target sites (TSs) in GluR2 and NR2B, inhibits NMDA-induced calcium influx in hippocampal neurons, and protects the brain from neuronal cell death following transient global ischemia and excitotoxic injury. MiR-223 deficiency results in higher levels of NR2B and GluR2, enhanced NMDA-induced calcium influx, and increased miniature excitatory postsynaptic currents in hippocampal neurons. In addition, the absence of MiR-223 leads to contextual, but not cued memory deficits and increased neuronal cell death following transient global ischemia and excitotoxicity. These data identify miR-223 as a major regulator of the expression of GluR2 and NR2B, and suggest a therapeutic role for miR-223 in stroke and other excitotoxic neuronal disorders.

show abstract

Section: Discussionmentioning

confidence: 56%

MicroRNA-223 is neuroprotective by targeting glutamate receptors

Harraz

Eacker²,

Wang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

257

183

View full text Add to dashboard Cite

show abstract

“…For example, even though they followed the protocols previously published in the field [15], Zhou et al [116] were recently unable to observe any preferential involvement of GluN2A-or GluN2B-NMDARs in excitotoxicity. By contrast, the group of Giles Hardingham demonstrates in a recent study that the CTD of NMDARs, rather than the channel's properties, is crucial in determining how they influence excitotoxicity [128]. They show in particular that the CTD of GluN2B-NMDARs enhances NMDA-induced excitotoxicity in cultures compared with the CTD of GluN2A-NMDARs, and that this selectivity is overcome when strong stimulation (100 mM NMDA) is used.…”

Section: Is Excitotoxicity Mediated By Extrasynaptic Nmdars?mentioning

confidence: 96%

Organization, control and function of extrasynaptic NMDA receptors

Papouin

Oliet

2014

Phil. Trans. R. Soc. B

154

123

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N-methyl D-aspartate receptors (NMDARs) exist in different forms owing to multiple combinations of subunits that can assemble into a functional receptor. In addition, they are located not only at synapses but also at extrasynaptic sites. There has been intense speculation over the past decade about whether specific NMDAR subtypes and/or locations are responsible for inducing synaptic plasticity and excitotoxicity. Here, we review the latest findings on the organization, subunit composition and endogenous control of NMDARs at extrasynaptic sites and consider their putative functions. Because astrocytes are capable of controlling NMDARs through the release of gliotransmitters, we also discuss the role of the glial environment in regulating the activity of these receptors.

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“…The reversal of the glutamate transporters under these conditions (Rossi et al, 2000;Grewer et al, 2008) further contributes to the extracellular accumulation of glutamate, with a consequent toxic overactivation of postsynaptic glutamate receptors (excitotoxicity) (Olney, 1969;Simon et al, 1984;Choi et al, 1987;Ferreira et al, 1996Ferreira et al, , 1998Martel et al, 2012). Upon oxygen and glucose deprivation (OGD), a well established in vitro model of global ischemia, glutamate is massively released by neurons, and the resulting increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i ) (Goldberg and Choi, 1993) causes a delayed neuronal cell death (calcium overload hypothesis) (Manev et al, 1989).…”

Section: Role Of Glutamatementioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

117

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults

Cited by 167 publications

References 72 publications

MicroRNA-223 is neuroprotective by targeting glutamate receptors

MicroRNA-223 is neuroprotective by targeting glutamate receptors

Organization, control and function of extrasynaptic NMDA receptors

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

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