Mechanism of partial agonist action at the NR1 subunit of NMDA receptors

Neuron. 2005 Jul 7;47(1):71-84. doi: 10.1016/j.neuron.2005.05.022.


Partial agonists produce submaximal activation of ligand-gated ion channels. To address the question of partial agonist action at the NR1 subunit of the NMDA receptor, we performed crystallographic and electrophysiological studies with 1-aminocyclopropane-1-carboxylic acid (ACPC), 1-aminocyclobutane-1-carboxylic acid (ACBC), and 1-aminocyclopentane-1-carboxylic acid (cycloleucine), three compounds with incrementally larger carbocyclic rings. Whereas ACPC and ACBC partially activate the NMDA receptor by 80% and 42%, respectively, their cocrystal structures of the NR1 ligand binding core show the same degree of domain closure as found in the complex with glycine, a full agonist, illustrating that the NR1 subunit provides a new paradigm for partial agonist action that is distinct from that of the evolutionarily related GluR2, AMPA-sensitive receptor. Cycloleucine behaves as an antagonist and stabilizes an open-cleft conformation. The NR1-cycloleucine complex forms a dimer that is similar to the GluR2 dimer, thereby suggesting a conserved mode of subunit-subunit interaction in AMPA and NMDA receptors.

Publication types

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

MeSH terms

  • Amino Acids, Cyclic / pharmacology
  • Animals
  • Binding, Competitive / drug effects
  • Crystallography, X-Ray
  • Cycloleucine / pharmacology
  • Electrophysiology
  • Excitatory Amino Acid Agonists / pharmacology*
  • Female
  • Kinetics
  • Ligands
  • Models, Molecular
  • Mutation
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Protein Conformation
  • Rats
  • Receptors, AMPA / metabolism
  • Receptors, Glycine / drug effects
  • Receptors, Glycine / metabolism
  • Receptors, N-Methyl-D-Aspartate / agonists*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Xenopus


  • Amino Acids, Cyclic
  • Excitatory Amino Acid Agonists
  • Ligands
  • NR1 NMDA receptor
  • Receptors, AMPA
  • Receptors, Glycine
  • Receptors, N-Methyl-D-Aspartate
  • Cycloleucine
  • 1-aminocyclobutanecarboxylic acid
  • 1-aminocyclopropane-1-carboxylic acid
  • glutamate receptor ionotropic, AMPA 2