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PDBsum entry 5h8f
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Transport protein
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PDB id
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5h8f
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References listed in PDB file
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Key reference
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Title
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Positive allosteric modulators of glun2a-Containing nmdars with distinct modes of action and impacts on circuit function.
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Authors
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D.H.Hackos,
P.J.Lupardus,
T.Grand,
Y.Chen,
T.M.Wang,
P.Reynen,
A.Gustafson,
H.J.Wallweber,
M.Volgraf,
B.D.Sellers,
J.B.Schwarz,
P.Paoletti,
M.Sheng,
Q.Zhou,
J.E.Hanson.
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Ref.
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Neuron, 2016,
89,
983-999.
[DOI no: ]
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PubMed id
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Abstract
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To enhance physiological function of NMDA receptors (NMDARs), we identified
positive allosteric modulators (PAMs) of NMDARs with selectivity for GluN2A
subunit-containing receptors. X-ray crystallography revealed a binding site at
the GluN1-GluN2A dimer interface of the extracellular ligand-binding domains
(LBDs). Despite the similarity between the LBDs of NMDARs and AMPA receptors
(AMPARs), GluN2A PAMs with good selectivity against AMPARs were identified.
Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B
NMDARs and with synaptically activated NMDARs in brain slices from wild-type
(WT), but not GluN2A knockout (KO), mice. Individual GluN2A PAMs exhibited
variable degrees of glutamate (Glu) dependence, impact on NMDAR Glu EC50, and
slowing of channel deactivation. These distinct PAMs also exhibited differential
impacts during synaptic plasticity induction. The identification of a new NMDAR
modulatory site and characterization of GluN2A-selective PAMs provide powerful
molecular tools to dissect NMDAR function and demonstrate the feasibility of a
therapeutically desirable type of NMDAR enhancement.
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