Molecular Determinants Controlling NMDA Receptor Synaptic Incorporation

Abstract

Synaptic incorporation of NMDARs is regulated by GluN2 subunits with different rules controlling GluN2A- and GluN2B-containing receptors; while GluN2B containing receptors are constitutively incorporated into synapses, GluN2A incorporation is activity-dependent. We expressed electrophysiologically tagged NMDARs in rat hippocampal slices in order to identify the molecular determinants controlling the mode of synaptic incorporation of NMDARs. Expressing chimeric GluN2 subunits, we identified a putative N-glycosylation site present in GluN2B, but not on GluN2A, as necessary and sufficient to drive NMDARs into synapses in an activity-independent manner. This suggests a novel mechanism for regulating activity driven changes and trafficking of NMDARs to the synapse.

Two N-glycosylation Sites in the GluN1 Subunit Are Essential for Releasing N-methyl-d-aspartate (NMDA) Receptors from the Endoplasmic Reticulum

“…Furthermore, we cannot exclude the possibility that the presence of N-glycans at nonconventional site(s) and/or the presence of other glycan structures (including O-glycans) may be essential for the trafficking and/or function of NMDARs. This is an important point given that a non-conventional N-glycosylation site in the GluN2B subunit is required for trafficking NMDARs to synapses in an activity-independent manner (41). In our experiments, we observed that mutating the other ten conventional N-glycosylation sites within the GluN1 subunit (instead of the Asn-203 and Asn-368 residues), diminishes the surface delivery of the NMDARs slightly differently in the tested cell types.…”

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

“…However, more recent data suggest that GluN2B is not only found out of the synapse, because it can form both di-or tri-heteromers at synaptic sites (Gray et al, 2011;Martinez-Turrillas et al, 2012;Storey et al, 2011;Wyllie et al, 2013).…”

Anti-NMDA Receptor Encephalitis Antibody Binding Is Dependent on Amino Acid Identity of a Small Region within the GluN1 Amino Terminal Domain

“…Still, it is becoming increasingly clear that glycosylation affects channels in a variety of ways: GluN2B glycosylation was recently identified as a determinant of synaptic integration (Storey et al, 2011), and ASIC1a trafficking is regulated by N-linked glycosylation (Jing et al, 2012). The regulation of glycosylation is still largely unknown; however, one potential mechanism of regulation is the restricted expression of different glycosyltransferases (Yamamoto et al, 2003).…”