title: Molecular mechanism of AMPA receptor noncompetitive antagonism.
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.
authors.affiliation: The Institute of Basic Dental Sciences, The Hebrew University-Hadassah Dental School, 91120 Jerusalem, Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Balannik
authors.forename: Frank S
authors.initials: FS
authors.lastname: Menniti
authors.forename: Ana V
authors.initials: AV
authors.lastname: Paternain
authors.forename: Juan
authors.initials: J
authors.lastname: Lerma
authors.forename: Yael
authors.initials: Y
authors.lastname: Stern-Bach
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008959:Models, Neurological; D016296:Mutagenesis / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000493:pharmacokinetics; D014982:Xenopus laevis
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D011799:Quinazolines; D018091:Receptors, AMPA; D014316:Tritium; D001569:Benzodiazepines; C079692:GYKI 53655; C418042:CP 465,022