title: Identification of amino acid residues in GluR1 responsible for ligand binding and desensitization.
abstract: Although GluR1(o) and GluR3(o) are homologous at the amino acid level, GluR3(o) desensitizes approximately threefold faster than GluR1(o). By creating chimeras of GluR1(o) and GluR3(o) and point amino acid exchanges in their S2 regions, two residues were identified to be critical for GluR1(o) desensitization: Y716 and the R/G RNA-edited site, R757. With creation of the double-point mutant (Y716F, R757G)GluR1(o), complete exchange of the desensitization rate of GluR1(o) to that of GluR3(o) was obtained. In addition, both the potency and affinity of the subtype-selective agonist bromohomoibotenic acid were exchanged by the Y716F mutation. A model is proposed of the AMPA receptor binding site whereby a hydrogen-bonding matrix of water molecules plays an important role in determining both ligand affinity and receptor desensitization properties. Residues Y716 in GluR1 and F728 in GluR3 differentially interact with this matrix to affect the binding affinity of some ligands, providing the possibility of developing subtype-selective compounds.
authors: Department of Pharmacology, EmoryUniversity, Atlanta, Georgia 30322, USA.
authors: T G
authors: TG
authors: Banke
authors: J R
authors: JR
authors: Greenwood
authors: J K
authors: JK
authors: Christensen
authors: T
authors: T
authors: Liljefors
authors: S F
authors: SF
authors: Traynelis
authors: A
authors: A
authors: Schousboe
authors: D S
authors: DS
authors: Pickering
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006860:Hydrogen Bonding; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D008845:Microinjections; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014867:Water / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D007051:Ibotenic Acid; D008024:Ligands; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D014867:Water; C104723:glutamate receptor ionotropic, AMPA 3; C023366:4-bromohomoibotenic acid