Identification of N-Methyl-d-aspartic Acid (NMDA) Receptor Subtype-specific Binding Sites That Mediate Direct Interactions with Scaffold Protein PSD-95

Abstract

Background: NMDA receptors are organized via scaffold proteins into macromolecular signaling complexes at synapses. Results: Novel binding sites that govern NMDA receptor/scaffold protein association have been delineated. Conclusion: The scaffold, PSD-95, binds to two sites that differ between NMDA receptor NR2A and NR2B subunits. Significance: The molecular basis of protein/protein interactions that contribute to organization of synaptic signaling complexes is extended and enhanced.

NMDA receptor triggered molecular cascade underlies compression-induced rapid dendritic spine plasticity in cortical neurons

“…Stable level, instead of disruption, of PSD95 within 3 h of compression argues for a role of PSD95 in clustering NMDA receptors (Gardoni et al, 2009). This is consistent with our proposition of a rapid insertion of NR1 to the postsynaptic membrane since PSD95 is necessary for the synaptic localization of NMDA receptors (Cousins and Stephenson, 2012). Insertion of NMDA receptors to the postsynaptic densities immediately after compression could have in turn triggered the depolymerization of actin in dendritic spines.…”

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

“…The GluN2A subunit additionally associates with the SH3 domain of PSD95 via a SH3 domain-binding motif, and the GluN2B subunit also interacts with PSD95 via a non-ESDV motif (1149)(1150)(1151)(1152)(1153)(1154)(1155)(1156)(1157). This suggests a differential association of NMDA receptor subtypes with PSD95 scaffold proteins which may contribute to the NMDAR organization and lateral mobility (Cousins and Stephenson, 2012;Kornau et al, 1995). The excitotoxicity-induced calpain-mediated cleavage of GluN2 subunits requires dissociation of the receptor subunit from PSD95.…”

Higher levels of phosphorylated Y1472 on GluN2B subunits in the frontal cortex of aged mice are associated with good spatial reference memory, but not cognitive flexibility

“…Although an increase in triheteromeric receptors would increase the PSD-95/GluN2B ratio, since GluN2A also binds PSD-95 (Xu 2011), there was no correlation between GluN2A and PSD-95 or spatial memory in the previous study (Zamzow et al 2013). It was speculated that the negative correlation between the PSD-95/ GluN2B ratio and spatial memory might be due to non-triheteromeric GluN2B-containing receptors interacting with PSD-95 and/or a possible shift of PSD-95 binding to the PSDP motif on GluN2B (Cousins and Stephenson 2012). The current data does not contradict this proposition.…”