TY - JOUR
T1 - Mechanism of partial agonist action at the NR1 subunit of NMDA receptors
AU - Inanobe, Atsushi
AU - Furukawa, Hiroyasu
AU - Gouaux, Eric
N1 - Funding Information:
X-ray diffraction data were measured at the X4A beamline at NSLS, and R. Abramowitz and X. Yang are acknowledged for assistance with the x-ray experiments. The rat NR1-1a and NR2B were generous gifts from S. Heinemann (Salk Institute, La Jolla, CA). A.I. was supported by the Yamanouchi Foundation for Research on Metabolic Disorders and the Uehara Memorial Foundation. This work was supported by the NIH. E.G. is an investigator with the Howard Hughes Medical Institute.
PY - 2005/7/7
Y1 - 2005/7/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=20444408992&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20444408992&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2005.05.022
DO - 10.1016/j.neuron.2005.05.022
M3 - Article
C2 - 15996549
AN - SCOPUS:20444408992
SN - 0896-6273
VL - 47
SP - 71
EP - 84
JO - Neuron
JF - Neuron
IS - 1
ER -