Molecular mechanism of AMPA receptor noncompetitive antagonism

Neuron. 2005 Oct 20;48(2):279-88. doi: 10.1016/j.neuron.2005.09.024.

Abstract

AMPA-type glutamate receptors are specifically inhibited by the noncompetitive antagonists GYKI-53655 and CP-465,022, which act through sites and mechanisms that are not understood. Using receptor mutagenesis, we found that these antagonists bind at the interface between the S1 and S2 glutamate binding core and channel transmembrane domains, specifically interacting with S1-M1 and S2-M4 linkers, thereby disrupting the transduction of agonist binding into channel opening. We also found that the antagonists' affinity is higher for agonist-unbound receptors than for activated nondesensitized receptors, further depending on the level of S1 and S2 domain closure. These results provide evidence for substantial conformational changes in the S1-M1 and S2-M4 linkers following agonist binding and channel opening, offering a conceptual frame to account for noncompetitive antagonism of AMPA receptors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodiazepines / pharmacology*
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Blotting, Western / methods
  • Brain / drug effects
  • Cell Line
  • Cloning, Molecular / methods
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology*
  • Models, Neurological
  • Mutagenesis / physiology
  • Patch-Clamp Techniques / methods
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Protein Conformation
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology*
  • Rats
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / chemistry
  • Receptors, AMPA / physiology*
  • Transfection / methods
  • Tritium / pharmacokinetics
  • Xenopus laevis

Substances

  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Peptide Fragments
  • Quinazolines
  • Receptors, AMPA
  • Tritium
  • Benzodiazepines
  • GYKI 53655
  • CP 465,022