Identification of amino acid residues in GluR1 responsible for ligand binding and desensitization

TY - JOUR

T1 - Identification of amino acid residues in GluR1 responsible for ligand binding and desensitization

AU - Banke, T G

AU - Greenwood, J R

AU - Christensen, J K

AU - Liljefors, T

AU - Traynelis, S F

AU - Schousboe, A

AU - Pickering, D S

AU - Pickering, Darryl

N1 - Keywords: Amino Acid Substitution; Animals; Binding Sites; Binding, Competitive; Cells, Cultured; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Glutamic Acid; Hydrogen Bonding; Ibotenic Acid; Ion Channel Gating; Ligands; Microinjections; Models, Molecular; Mutagenesis, Site-Directed; Oocytes; Patch-Clamp Techniques; Receptors, AMPA; Recombinant Fusion Proteins; Structure-Activity Relationship; Water; Xenopus laevis

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

M3 - Journal article

C2 - 11312290

SN - 0270-6474

VL - 21

SP - 3052

EP - 3062

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

IS - 9

ER -