THE two-electrode voltage-clamp technique was used to evaluate Zn block of current activated by γ-aminobutyric acid (GABA) in Xenopus oocytes injected with cRNA coding for α1 β3 γ2, α2 β3 γ2, or α3 β3 γ2 subunits of the GABAA receptor (GABAAR). cDNA coded for the human form of α1, α2, β3 and γ2L subunits. α3 subunit cDNA was obtained from an African green monkey library. Zn significantly inhibited the current evoked by application of GABA. Maximal inhibition was greater in α2-and α3 containing GABAARs than in α1-containing GABAARs (51 ± 1% and 53 ± 2% vs 19 ± 2%, respectively). The IC50 for Zn was smaller in α1 than in α2 or α3 GABAARs (1.2 ± 0.3 μM vs 7 ± 1 and 9 ± 1 μM, respectively). Zn shifted the concentration-response curve of GABA to the right in a parallel manner. These data suggest that Zn reduces the amplitude of current evoked at γ2 subunit containing GABAARs through an allosteric mechanism.