Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists
Cell. 2012-08-01; 150(3): 633-646
DOI: 10.1016/j.cell.2012.06.029
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1. Cell. 2012 Aug 3;150(3):633-46. doi: 10.1016/j.cell.2012.06.029.
Synaptic and extrasynaptic NMDA receptors are gated by different endogenous
coagonists.
Papouin T(1), Ladépêche L, Ruel J, Sacchi S, Labasque M, Hanini M, Groc L,
Pollegioni L, Mothet JP, Oliet SH.
Author information:
(1)INSERM U862, Neurocentre Magendie, 33077 Bordeaux, France.
Comment in
Cell. 2012 Aug 3;150(3):455-6.
Nat Rev Neurosci. 2012 Oct;13(10):666-7.
N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at
synaptic and extrasynaptic locations, where they are believed to mediate distinct
physiological and pathological processes. Activation of NMDARs requires glutamate
and a coagonist whose nature and impact on NMDAR physiology remain elusive. We
report that synaptic and extrasynaptic NMDARs are gated by different endogenous
coagonists, d-serine and glycine, respectively. The regionalized availability of
the coagonists matches the preferential affinity of synaptic NMDARs for d-serine
and extrasynaptic NMDARs for glycine. Furthermore, glycine and d-serine inhibit
NMDAR surface trafficking in a subunit-dependent manner, which is likely to
influence NMDARs subcellular location. Taking advantage of this coagonist
segregation, we demonstrate that long-term potentiation and NMDA-induced
neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression
requires both synaptic and extrasynaptic receptors. Our observations provide key
insights into the operating mode of NMDARs, emphasizing functional distinctions
between synaptic and extrasynaptic NMDARs in brain physiology.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2012.06.029
PMID: 22863013 [Indexed for MEDLINE]