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J Biol Chem, Vol. 275, Issue 19, 14198-14204, May 12, 2000

Tyrosine 62 of the gamma -Aminobutyric Acid Type A Receptor beta 2 Subunit Is an Important Determinant of High Affinity Agonist Binding*

J. Glen NewellDagger §, Martin DaviesDagger , Alan N. BatesonDagger ||**, and Susan M. J. DunnDagger §§

From the Dagger  Department of Pharmacology,  Division of Neuroscience, and the || Department of Psychiatry, 9-70 Medical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

The gamma -aminobutyric acid type A receptor (GABAAR) carries both high (KD = 10-30 nM) and low (KD = 0.1-1.0 µM) affinity binding sites for agonists. We have used site-directed mutagenesis to identify a specific residue in the rat beta 2 subunit that is involved in high affinity agonist binding. Tyrosine residues at positions 62 and 74 were mutated to either phenylalanine or serine and the effects on ligand binding and ion channel activation were investigated after the expression of mutant subunits with wild-type alpha 1 and gamma 2 subunits in tsA201 cells or in Xenopus oocytes. None of the mutations affected [3H]Ro15-4513 binding or impaired allosteric interactions between the low affinity GABA and benzodiazepine sites. Although mutations at position 74 had little effect on [3H]muscimol binding, the Y62F mutation decreased the affinity of the high affinity [3H]muscimol binding sites by ~6-fold, and the Y62S mutation led to a loss of detectable high affinity binding sites. After expression in oocytes, the EC50 values for both muscimol and GABA-induced activation of Y62F and Y62S receptors were increased by 2- and 6-fold compared with the wild-type. We conclude that Tyr-62 of the beta  subunit is an important determinant for high affinity agonist binding to the GABAA receptor.

* This work was supported by the Medical Research Council of Canada and the Alberta Heritage Foundation Medical Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Holds a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada and an award from the Neuroscience Canada Foundation.

** An Alberta Heritage Foundation Medical Research Scholar.

§§ Held a Medical Research Council Scientist award. To whom correspondence and reprint requests should be addressed. Tel.: 780-492-3414; Fax: 780-492-4325; E-mail: susan.dunn@ualberta.ca.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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