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

Atsushi Inanobe, Hiroyasu Furukawa, Eric Gouaux

Research output: Contribution to journalArticle

142 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)71-84
Number of pages14
JournalNeuron
Volume47
Issue number1
DOIs
StatePublished - Jul 7 2005
Externally publishedYes

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Cycloleucine
Carboxylic Acids
AMPA Receptors
N-Methyl-D-Aspartate Receptors
Ligand-Gated Ion Channels
Glycine
Ligands
NR1 NMDA receptor
1-aminocyclopropane-1-carboxylic acid

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. / Inanobe, Atsushi; Furukawa, Hiroyasu; Gouaux, Eric.

In: Neuron, Vol. 47, No. 1, 07.07.2005, p. 71-84.

Research output: Contribution to journalArticle

Inanobe, Atsushi ; Furukawa, Hiroyasu ; Gouaux, Eric. / Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. In: Neuron. 2005 ; Vol. 47, No. 1. pp. 71-84.
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