Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants

@article{Yan2020CouplingON,
  title={Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants},
  author={Jing Yan and C. Peter Bengtson and Bettina Buchthal and Anna M. Hagenston and Hilmar Bading},
  journal={Science},
  year={2020},
  volume={370}
}
Interface targeting skirts excitotoxicity Nearly all attempts to use traditional N-methyl-d-aspartate receptor (NMDAR) antagonists to treat neurodegenerative diseases have failed. This is because NMDARs are not only promoters of neuronal death but also have essential physiological roles in synaptic plasticity and cognitive functions such as learning and memory. Yan et al. explored the structural basis of NMDAR coupling to neuronal cell death (see the Perspective by Jones). The death-promoting… 
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References

SHOWING 1-10 OF 55 REFERENCES
Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors
Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders
New advances in NMDA receptor pharmacology.
Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond
  • S. Lipton
  • Biology
    Nature Reviews Drug Discovery
  • 2006
TLDR
The molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca2+ influx through the receptor's associated ion channel and consequent free-radical formation is reviewed.
Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
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
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
TLDR
Perturbations in the balance between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington's disease, and could be a common theme in the aetiology of neurodegenerative diseases.
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.
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