Allosteric Interactions between NMDA Receptor Subunits Shape the Developmental Shift in Channel Properties

During development of the central nervous system, there is a shift in the subunit composition of NMDA receptors (NMDARs) resulting in a dramatic acceleration of NMDAR-mediated synaptic currents. This shift coincides with upregulation of the GluN2A subunit and triheteromeric GluN1/2A/2B receptors with fast deactivation kinetics, whereas expression of diheteromeric GluN1/2B receptors with slower deactivation kinetics is decreased. Here, we show that allosteric interactions occur between the glutamate-binding GluN2 subunits in triheteromeric GluN1/2A/2B NMDARs. This allosterism is dominated by the GluN2A subunit and results in functional properties not predicted by those of diheteromeric GluN1/2A and GluN1/2B NMDARs. These findings suggest that GluN1/2A/2B NMDARs may maintain some signaling properties of the GluN2B subunit while having the kinetic properties of GluN1/2A NMDARs and highlight the complexity in NMDAR signaling created by diversity in subunit composition. •Allosterism occurs between GluN2 subunits in triheteromeric GluN1/2A/2B NMDARs•These allosteric interactions are asymmetric and dominated by the GluN2A subunit•GluN2A-dominant interactions span multiple domains in the NMDAR•The allosteric interactions endow GluN1/2A/2B with the function of GluN1/2A NMDARs Sun et al. demonstrate asymmetric inter-GluN2 allosteric interactions within triheteromeric GluN1/2A/2B NMDARs that result in open probability and deactivation kinetics similar to diheteromeric GluN1/2A receptors. This finding highlights the complexity in NMDAR signaling endowed by diversity in subunit composition.