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J. Biol. Chem., Vol. 279, Issue 34, 35193-35200, August 20, 2004

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Four Amino Acids in the Subunits Determine the -Aminobutyric Acid Sensitivities of GABA_A Receptor Subtypes^*

Ingo Böhme, Holger Rabe, and Hartmut Lüddens¶

From the Laboratory of Molecular Biology, Department of Psychiatry, University of Mainz, Untere Zahlbacher Strasse 8, 55131 Mainz, Germany

GABA_A receptors, mediators of fast inhibitory neurotransmission, are heteropentameric assemblies from a large array of subunits. Differences in the sensitivity of receptor subtypes to endogenous GABA may permit subunit-dependent finely tuned responsiveness to the same GABAergic inputs. Using both radioligand binding and electrophysiology combined with mutagenesis, we identified a domain of four amino acids within the subunits that mediates the distinct sensitivities to GABA allowing their selective switch between 32 combinations. Replacing this domain in 3 by the corresponding segments of 1–5 resulted in mutant receptors displaying the GABA EC₅₀ values of the respective wild-type receptors. Vice versa, the 3 motif forced the low sensitivity to GABA of 3 upon 132, 432, and 532. Binding of the GABA agonist [³H]muscimol was not affected by the exchange of the motif between 1 and 3 subunits. Thus, the equilibrium binding pocket is maintained upon replacement of the four amino acids. Taken together our data suggest that the identified motifs contribute to a structure involved in the transduction of the binding signal rather than to the binding itself.

Received for publication, May 20, 2004 , and in revised form, June 14, 2004.

^* This work was supported by Deutsche Forschungsgemeinschaft and Mainzer Forschungsförderungsprogramm of the University of Mainz. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this study

Recipient of a grant from the "Stiftung Rheinland-Pfalz für Innovation."

^¶ To whom correspondence should be addressed: Dept. of Psychiatry, University of Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany. Tel.: 49-6131-175372; E-mail: lueddens{at}uni-mainz.de.

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