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

Although GluR1(o) and GluR3(o) are homologous at the amino acid level, GluR 3(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) desens itization: Y716 and the R/G RNA-edited site, R757. With creation of the dou ble-point mutant (Y716F, R757G) GluR1(o), complete exchange of the desensit ization rate of GluR1(o) to that of GluR3(o) was obtained. In addition, bot h the potency and affinity of the subtype-selective agonist bromohomoiboten ic acid were exchanged by the Y716F mutation. A model is proposed of the AM PA receptor binding site whereby a hydrogen-bonding matrix of water molecul es plays an important role in determining both ligand affinity and receptor desensitization properties. Residues Y716 in GluR1 and F728 in GluR3 diffe rentially interact with this matrix to affect the binding affinity of some ligands, providing the possibility of developing subtype-selective compound s.