Proton Modulation of 1 3 GABAA Receptor Channel Gating and Desensitization

Feng, Hua-Jun and Robert L. Macdonald. Proton modulation of 1 3 GABAA receptor channel gating and desensitization. J Neurophysiol 92: 1577–1585, 2004. First published May 19, 2004; 10.1152/jn.00285.2004. GABAA receptor currents are phasic and desensitizing, whereas GABAA receptor currents are tonic and have no fast desensitization. receptors are subsynaptic and mediate phasic inhibition, whereas receptors are extraor perisynaptic and mediate tonic inhibition. Given the different roles of these GABAA receptor isoforms and the fact that GABAA receptors are allosterically regulated by extracellular pH in a subunit-dependent manner, we compared the effects of changing pH on rat or 2L subunit–containing GABAA receptor currents. Human embryonic kidney cells (HEK293T) were transfected with cDNAs encoding rat 1, 3, 2L, or GABAA receptor subunits in several binary and ternary combinations, and whole cell and single channel patch-clamp recordings were obtained. Lowering pH substantially enhanced 1 3 receptor currents. This effect was significantly more pronounced for ternary 1 3 receptors, whereas ternary 1 3 2L receptors were relatively insensitive to lowered pH. Lowering pH did not affect the extent of desensitization of 1 3 and 1 3 2L receptor currents, but significantly increased the extent of desensitization of 1 3 receptor currents. Lowering pH prolonged deactivation of 1 3 and 1 3 receptor currents and enhanced the “steady-state” currents of 1 3 receptors evoked by long-duration (28 s) GABA applications. Lowering pH significantly increased mean open duration of 1 3 steadystate single channel currents due to introduction of a longer-duration open state, suggesting that low pH enhances 1 3 receptor steadystate currents by modifying GABAA receptor gating properties.