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Proton Modulation of 13 GABA_A Receptor Channel Gating and Desensitization

Departments of ¹Neurology, ²Molecular Physiology and Biophysics, and ³Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37212

Submitted 22 March 2004; accepted in final form 13 May 2004

GABA_A receptor currents are phasic and desensitizing, whereas GABA_A receptor currents are tonic and have no fast desensitization. receptors are subsynaptic and mediate phasic inhibition, whereas receptors are extra- or perisynaptic and mediate tonic inhibition. Given the different roles of these GABA_A receptor isoforms and the fact that GABA_A 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 GABA_A receptor currents. Human embryonic kidney cells (HEK293T) were transfected with cDNAs encoding rat 1, 3, 2L, or GABA_A receptor subunits in several binary and ternary combinations, and whole cell and single channel patch-clamp recordings were obtained. Lowering pH substantially enhanced 13 receptor currents. This effect was significantly more pronounced for ternary 13 receptors, whereas ternary 132L receptors were relatively insensitive to lowered pH. Lowering pH did not affect the extent of desensitization of 13 and 132L receptor currents, but significantly increased the extent of desensitization of 13 receptor currents. Lowering pH prolonged deactivation of 13 and 13 receptor currents and enhanced the "steady-state" currents of 13 receptors evoked by long-duration (28 s) GABA applications. Lowering pH significantly increased mean open duration of 13 steady-state single channel currents due to introduction of a longer-duration open state, suggesting that low pH enhances 13 receptor steady-state currents by modifying GABA_A receptor gating properties.

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