Mechanism of partial agonist action at the NR1 subunit of NMDA receptors.
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.
Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, NY 10032, USA.
Atsushi
A
Inanobe
Hiroyasu
H
Furukawa
Eric
E
Gouaux
D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D018360:Crystallography, X-Ray; D003515:Cycloleucine / Q000494:pharmacology; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011487:Protein Conformation; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D018009:Receptors, Glycine / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D014981:Xenopus
D000598:Amino Acids, Cyclic; D018690:Excitatory Amino Acid Agonists; D008024:Ligands; C409466:NR1 NMDA receptor; D018091:Receptors, AMPA; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D003515:Cycloleucine; C016987:1-aminocyclobutanecarboxylic acid; C023863:1-aminocyclopropane-1-carboxylic acid; C104722:glutamate receptor ionotropic, AMPA 2