Mechanism of positive allosteric modulators acting on AMPA receptors

Rongsheng Jin, Suzanne Clark, Autumn M. Weeks, Joshua T. Dudman, Eric Gouaux, Kathryn M. Partin

Research output: Contribution to journalArticle

183 Citations (Scopus)

Abstract

Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1,3-oxazino benzo-1,4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the "hinge" in the ligand-binding core "clamshell" that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.

Original languageEnglish (US)
Pages (from-to)9027-9036
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number39
DOIs
StatePublished - Sep 28 2005

Fingerprint

aniracetam
AMPA Receptors
Glutamate Receptors
Glutamic Acid
Ligands
Ligand-Gated Ion Channels
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Kainic Acid
Electrophysiology
N-Methyl-D-Aspartate Receptors
Point Mutation
Neurodegenerative Diseases
Alzheimer Disease
Binding Sites
Depression

Keywords

  • Aniracetam
  • Crystallography
  • CX614
  • Cyclothiazide
  • Deactivation
  • Desensitization
  • Glutamate receptor
  • Kinetics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mechanism of positive allosteric modulators acting on AMPA receptors. / Jin, Rongsheng; Clark, Suzanne; Weeks, Autumn M.; Dudman, Joshua T.; Gouaux, Eric; Partin, Kathryn M.

In: Journal of Neuroscience, Vol. 25, No. 39, 28.09.2005, p. 9027-9036.

Research output: Contribution to journalArticle

Jin, Rongsheng ; Clark, Suzanne ; Weeks, Autumn M. ; Dudman, Joshua T. ; Gouaux, Eric ; Partin, Kathryn M. / Mechanism of positive allosteric modulators acting on AMPA receptors. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 39. pp. 9027-9036.
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