1 Proton Modulation of D 1 E 3 G Gabaa Receptor Channel Gating and Desensitization

αβγ GABAA receptor currents are phasic and desensitizing while αβδ GABAA receptor currents are tonic and have no fast desensitization. αβγ receptors are subsynaptic and mediate phasic inhibition while αβδ receptors are extra or peri-synaptic and mediate tonic inhibition. Given the different roles of these GABAA receptor isoforms and that GABAA receptors are allosterically regulated by extracellular pH in a subunit-dependent manner, we compared the effects of changing pH on rat δ or γ2L subunit-containing GABAA receptor currents. Human embryonic kidney cells (HEK293T) were transfected with cDNAs encoding rat α1, β3, γ2L or δ GABAA receptor subunits in several binary and ternary combinations, and whole cell and single channel patch clamp recordings were obtained. Lowering pH substantially enhanced α1β3 receptor currents. This effect was significantly more pronounced for ternary α1β3δ receptors, while ternary α1β3γ2L receptors were relatively insensitive to lowered pH. Lowing pH did not affect the extent of desensitization of α1β3 and α1β3γ2L receptor currents, but significantly increased the extent of desensitization of α1β3δ receptor currents. Lowering pH prolonged deactivation of α1β3 and α1β3δ receptor currents and enhanced the “steady state” currents of α1β3δ receptors evoked by long-duration (28 sec) GABA applications. Lowering pH significantly increased mean open duration of α1β3δ steady state single channel currents due to introduction of a longer-duration open state, suggesting that low pH enhances α1β3δ receptor “steady state” currents by modifying GABAA receptor gating properties.