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The Journal of Neuroscience, May 1, 2001, 21(9):3052-3062

Identification of Amino Acid Residues in GluR1 Responsible for Ligand Binding and Desensitization

T. G. Banke³, J. R. Greenwood², J. K. Christensen¹, T. Liljefors², S. F. Traynelis³, A. Schousboe¹, and Darryl S. Pickering¹

Departments of ¹ Pharmacology and ² Medicinal Chemistry, NeuroScience PharmaBiotech Research Center,The Royal Danish School of Pharmacy, DK-2100 Copenhagen, Denmark, and ³ Department of Pharmacology, Emory University, Atlanta, Georgia 30322

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.

Key words: AMPA receptor; desensitization; binding site; GluR1; GluR2; GluR3; GluR4 agonist subtype-selectivity; mutant receptors

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2193052-11$05.00/0

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