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

Neuron. 2017 Apr 5;94(1):58-64.e3. doi: 10.1016/j.neuron.2017.03.018.

Abstract

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.

Keywords: GluN2 subunit; Triheteromeric NMDA receptors; allosteric interaction; amino-terminal domain; crosslinking; excitatory synaptic transmission; glutamate; open probability; receptor deactivation.

MeSH terms

  • Allosteric Regulation / genetics*
  • Animals
  • Endoplasmic Reticulum
  • Gene Expression Regulation, Developmental*
  • Glutamic Acid / metabolism
  • HEK293 Cells
  • Humans
  • Neuronal Plasticity
  • Oocytes / metabolism*
  • Patch-Clamp Techniques
  • Protein Subunits
  • Rats
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synaptic Transmission
  • Xenopus laevis

Substances

  • NMDA receptor A1
  • NR2B NMDA receptor
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • N-methyl D-aspartate receptor subtype 2A