Subunit arrangement and function in NMDA receptors

@article{Furukawa2005SubunitAA,
  title={Subunit arrangement and function in NMDA receptors},
  author={Hiro Furukawa and Satinder K. Singh and Romina Mancusso and Eric Gouaux},
  journal={Nature},
  year={2005},
  volume={438},
  pages={185-192}
}
Excitatory neurotransmission mediated by NMDA (N-methyl-d-aspartate) receptors is fundamental to the physiology of the mammalian central nervous system. These receptors are heteromeric ion channels that for activation require binding of glycine and glutamate to the NR1 and NR2 subunits, respectively. NMDA receptor function is characterized by slow channel opening and deactivation, and the resulting influx of cations initiates signal transduction cascades that are crucial to higher functions… 
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References

SHOWING 1-10 OF 55 REFERENCES
Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand‐binding core
TLDR
The cocrystal structures of the NR1 S1S2 ligand‐binding core with the agonists glycine and D‐serine (DS), the partial agonist D‐cycloserine (DCS) and the antagonist 5,7‐dichlorokynurenic acid (DCKA) are described.
Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors
TLDR
C cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam or CX614 are presented, suggesting that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.
Mechanism of activation and selectivity in a ligand-gated ion channel: structural and functional studies of GluR2 and quisqualate.
TLDR
A detailed comparison of the three agonist complexes reveals distinct binding mechanisms, particularly in the region of a hydrophobic pocket that is proximal to the anionic gamma-substituents, and demonstrates the importance of agonist-water-receptor interactions.
Mechanism of glutamate receptor desensitization
TLDR
Using the GluR2 AMPA-sensitive glutamate receptor, it is shown that the ligand-binding cores form dimers and that stabilization of the intradimer interface by either mutations or allosteric modulators reduces desensitization.
Studies of NMDA Receptor Function and Stoichiometry with Truncated and Tandem Subunits
TLDR
It is shown here that truncated NMDA receptor subunits may be partially rescued by coexpressing the final TM and tail as a separate protein, and may redirect future studies into the mechanism of binding and gating in these receptors toward schemes including dimers.
NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones
TLDR
It is directly demonstrated that excitatory amino acids acting at NMDA receptors on spinal cord neurones increase the intracellular Ca2+ activity, measured using the indicator dye arsenazo III, and that this is the result of Ca2- influx through NMDA receptor channels.
Structure of a glutamate-receptor ligand-binding core in complex with kainate
TLDR
The bilobed structure shows the determinants of receptor–agonist interactions and how ligand-binding specificity and affinity are altered by remote residues and the redox state of the conserved disulphide bond.
Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones
TLDR
Using voltage-clamp experiments on mouse spinal cord neurones, it is shown that the voltage-sensitivity of NMDA action is greatly reduced on the withdrawal of physiological concentrations (∼1 mM) of Mg2+ from the extracellular fluid, providing further evidence that Mg 2+ blocks inward current flow through ion channels linked to NMDA receptors.
Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents
TLDR
In cultured hippocampal neurons, it is found that the NMDA receptor antagonist D-2-amino-5-phosphonopentanoate has no effect on the slow e.p.s.c. when rapidly applied after activation of the synapse, suggesting that rebinding of glutamate does not occur.
Mechanism of Partial Agonist Action at the NR1 Subunit of NMDA Receptors
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4
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