Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways

@article{Hardingham2002ExtrasynapticNO,
  title={Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways},
  author={Giles E. Hardingham and Yuko Fukunaga and Hilmar Bading},
  journal={Nature Neuroscience},
  year={2002},
  volume={5},
  pages={405-414}
}
Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or… 
Extrasynaptic NMDA receptors: mediators of excitotoxic cell death
TLDR
As extrasynaptic NMDA receptors are thought to be activated following hypoxic/ischemic insults, specific blockade of ExtrasynapticNMDA receptors or its signaling complex may efficiently reduce neuron loss following stroke.
Extrasynaptic NMDA receptors : mediators of excitotoxic cell
TLDR
As extrasynaptic NMDA receptors are thought to be activated following hypoxic/ischemic insults, specific blockade of ExtrasynapticNMDA receptors or their signaling complex may efficiently reduce neuron loss following stroke.
NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors
TLDR
It is demonstrated that activation of NMDAR bi-directionally regulated cell fate through stimulating pro-survival or pro-death signaling, and genome-wide examination demonstrated that the activation of syn- and ex-NMDAR lead to significant overlapping rather than counteracting transcriptional responses.
Recruiting extrasynaptic NMDA receptors augments synaptic signaling.
TLDR
These results demonstrate that "extrasynaptic" NMDARs regularly participate in synaptic transmission, and play a vital role in synaptic physiology, calling into question their status as "extraynaptic".
Preconditioning Doses of NMDA Promote Neuroprotection by Enhancing Neuronal Excitability
TLDR
Exposure to low preconditioning doses of NMDA results in preferential activation of synaptic NMDA receptors because of a dramatic increase in action potential firing, in apparent contradiction with recent findings that extrasynaptic NMDA receptor signaling exerts a dominant inhibitory effect on prosurvival signaling from synapticNMDA receptors.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 60 REFERENCES
Developmentally Regulated NMDA Receptor-Dependent Dephosphorylation of cAMP Response Element-Binding Protein (CREB) in Hippocampal Neurons
TLDR
It is suggested that, during neuronal maturation, NMDA receptor activation becomes linked specifically to protein phosphatases that act on Ser-133 of CREB, contributing to the changes in neural plasticity observed during brain development.
Glutamate-mediated astrocyte–neuron signalling
TLDR
Astrocytes regulate neuronal calcium levels through the calcium-dependent release of glutamate, and an NMDA (N-methyl-d-aspartate) receptor-mediated increase in neuronal calcium is demonstrated.
Glutamate release in severe brain ischaemia is mainly by reversed uptake
TLDR
It is demonstrated that transporter-mediated glutamate homeostasis fails dramatically in ischaemia: instead of removing extracellular glutamate to protect neurons, transporters release glutamate, triggering neuronal death.
Mitochondrial Dysfunction Is a Primary Event in Glutamate Neurotoxicity
TLDR
Early mitochondrial damage plays a key role in induction of glutamate neurotoxicity, and blockade of the mitochondrial permeability transition pore by cyclosporin A allows complete recovery of ΔΨ and prevents cell death.
A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication
TLDR
A calcium pool in the immediate vicinity of synaptic NMDA receptors is the on switch for extracellular signal-regulated kinase (ERK1/2)-mediated synapse-to-nucleus signaling; this signal propagates to the nucleus independently of global increases in calcium concentration, stimulates SRE-dependent gene expression and prolongs the transcriptionally active state of CREB following brief synaptic stimuli.
The Incorporation of NMDA Receptors with a Distinct Subunit Composition at Nascent Hippocampal Synapses In Vitro
TLDR
The data indicate that the synaptic NMDA receptor complement changes quickly after synapse formation, and suggests that synapses containing predominately NR1/NR2B heteromers represent “immature” sites, whereas mature sites express NMDA receptors with a distinct, presumably triheteromeric, subunit composition.
Glutamate-induced neuron death requires mitochondrial calcium uptake
TLDR
Results indicate that very high levels of cytoplasmic calcium are not necessarily toxic to forebrain neurons, and that potential-driven uptake of calcium into mitochondria is required to trigger NMDA-receptor-stimulated neuronal death.
Transcription-dependent neuronal plasticity: The nuclear calcium hypothesis.
  • H. Bading
  • Biology
    European journal of biochemistry
  • 2000
TLDR
Electrical activity causes long-lasting, transcription-dependent changes in neuronal functions when synaptically evoked calcium transients associated with the stimulation propagate to the nucleus; gene transcription activated by dendritic calcium signals only is insufficient to consolidate functional alterations long-term.
Proteomic analysis of NMDA receptor–adhesion protein signaling complexes
TLDR
Proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain indicates the NRC also participates in human cognition.
...
1
2
3
4
5
...