Protons inhibit Cl− conductance by direct or allosteric interaction with the GABA-binding site in the rat recombinant α1β2γ2L and α1β2 GABAA receptor

Functional roles of external pH on the Cl− conductance were examined on Xenopus oocytes expressing rat recombinant α1β2γ2L and α1β2 GABAA receptors. Acidic pH inhibited GABA-response in a reversible and concentration-dependent manner, significantly increasing the EC50 without appreciably changing the slope or maximal currents induced by GABA in the α1β2γ2L and α1β2 receptors. In contrast, protonation did not influence the pentobarbital-gated currents in the α1β2γ2L receptors, suggesting that protons do not modulate channel activity by directly affecting the channel gating process. Protons competitively inhibited the bicuculline-induced antagonism on GABA in the α1β2γ2L receptors. The data support the hypothesis that protons inhibit GABAA receptor function by direct or allosteric interaction with the GABA-binding site.