Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 150 (3), 633-46

Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists

Affiliations

Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists

Thomas Papouin et al. Cell.

Abstract

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.

Comment in

Similar articles

See all similar articles

Cited by 196 PubMed Central articles

See all "Cited by" articles

Publication types

LinkOut - more resources

Feedback