Pharmacology of triheteromeric N-Methyl-D-Aspartate Receptors

Neurosci Lett. 2016 Mar 23;617:240-6. doi: 10.1016/j.neulet.2016.02.032. Epub 2016 Feb 23.


The N-Methyl-D-Aspartate Receptors (NMDARs) are heteromeric cation channels involved in learning, memory, and synaptic plasticity, and their dysregulation leads to various neurodegenerative disorders. Recent evidence has shown that apart from the GluN1/GluN2A and GluN1/GluN2B diheteromeric ion channels, the NMDAR also exists as a GluN1/GluN2A/GluN2B triheteromeric channel that occupies the majority of the synaptic space. These GluN1/GluN2A/GluN2B triheteromers exhibit pharmacological and electrophysiological properties that are distinct from the GluN1/GluN2A and GluN1/GluN2B diheteromeric subtypes. However, these receptors have not been characterized with regards to their inhibition by conantokins, as well as their allosteric modulation by polyamines and extracellular protons. Here, we show that the GluN1/GluN2A/GluN2B triheteromeric channels showed less sensitivity to GluN2B-specific conantokin (con)-G and con-RlB, and subunit non-specific con-T, compared to the GluN2A-specific inhibitor TCN-201. Also, spermine modulation of GluN1/GluN2A/GluN2B triheteromers switched its nature from potentiation to inhibition in a pH dependent manner, and was 2.5-fold slower compared to the GluN1/GluN2B diheteromeric channels. Unraveling the distinctive functional attributes of the GluN1/GluN2A/GluN2B triheteromers is physiologically relevant since they form an integral part of the synapse, which will aid in understanding spermine/pH-dependent potentiation of these receptors in pathological settings.

Keywords: Contanokins; Diheteromers; NMDAR; Pharmacology; Triheteromers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Conotoxins / pharmacology
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mollusk Venoms / pharmacology
  • Patch-Clamp Techniques
  • Peptides / pharmacology
  • Protein Multimerization
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Spermine / pharmacology
  • Sulfonamides / pharmacology


  • Conotoxins
  • Intercellular Signaling Peptides and Proteins
  • Mollusk Venoms
  • NR1 NMDA receptor
  • NR2B NMDA receptor
  • Peptides
  • Receptors, N-Methyl-D-Aspartate
  • Sulfonamides
  • TCN 201
  • conantokin-T
  • Spermine
  • conotoxin GV
  • N-methyl D-aspartate receptor subtype 2A