Kinetic contributions to gating by interactions unique to N-methyl-D-aspartate (NMDA) receptors

J Biol Chem. 2015 Oct 30;290(44):26846-55. doi: 10.1074/jbc.M115.678656. Epub 2015 Sep 14.


Among glutamate-gated channels, NMDA receptors produce currents that subside with unusually slow kinetics, and this feature is essential to the physiology of central excitatory synapses. Relative to the homologous AMPA and kainate receptors, NMDA receptors have additional intersubunit contacts in the ligand binding domain that occur at both conserved and non-conserved sites. We examined GluN1/GluN2A single-channel currents with kinetic analyses and modeling to probe these class-specific intersubunit interactions for their role in glutamate binding and receptor gating. We found that substitutions that eliminate such interactions at non-conserved sites reduced stationary gating, accelerated deactivation, and imparted sensitivity to aniracetam, an AMPA receptor-selective positive modulator. Abolishing unique contacts at conserved sites also reduced stationary gating and accelerated deactivation. These results show that contacts specific to NMDA receptors, which brace the heterodimer interface within the ligand binding domain, stabilize actively gating receptor conformations and result in longer bursts and slower deactivations. They support the view that the strength of the heterodimer interface modulates gating in both NMDA and non-NMDA receptors and that unique interactions at this interface are responsible in part for basic differences between the kinetics of NMDA and non-NMDA currents at glutamatergic synapses.

Keywords: N-methyl-d-aspartate receptor (NMDA receptor, NMDAR); activation mechanism; gating; ionotropic glutamate receptor; kinetics; receptor structure-function; synaptic transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Biological Transport
  • Crystallography, X-Ray
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Ion Channel Gating
  • Ligands
  • Membrane Potentials / physiology*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Nootropic Agents / chemistry*
  • Nootropic Agents / metabolism
  • Patch-Clamp Techniques
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Pyrrolidinones / chemistry*
  • Pyrrolidinones / metabolism
  • Rats
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / chemistry*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • Ligands
  • NMDA receptor A1
  • Nootropic Agents
  • Pyrrolidinones
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • aniracetam
  • N-methyl D-aspartate receptor subtype 2A

Associated data

  • PDB/2A5T
  • PDB/2AL5