Pentobarbital Differentially Modulates α1β3δ and α1β3γ2L GABAA Receptor Currents

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Abstract
GABAA receptors are modulated by a variety of compounds, including the neurosteroids and barbiturates. Although the effects of barbiturates on αβγ isoforms, thought to dominate phasic (synaptic) GABAergic inhibition, have been extensively studied, the effects of pentobarbital on kinetic properties of αβδ GABAA receptors, thought to mediate tonic (extra- or perisynaptic) inhibition, are unknown. Using ultrafast drug delivery and single channel recording techniques, we demonstrate isoform-specific pentobarbital modulation of low-efficacy, minimally desensitizing α1β3 currents and high-efficacy, rapidly desensitizing α1β3γ2L currents. Specifically, with saturating concentrations of GABA, pentobarbital substantially potentiated peak α1β3δ receptor currents but failed to potentiate peak α1β3γ2L receptor currents. Also, pentobarbital had opposite effects on the desensitization of α1β3δ (increased) and α1β3γ2L (decreased) receptor currents evoked by saturating GABA. Pentobarbital increased steady-state α1β3δ receptor single channel open duration primarily by introducing a longer duration open state, whereas for α1β3γ2L receptor channels, pentobarbital increased mean open duration by increasing the proportion and duration of the longest open state. The data support previous suggestions that GABA may be a partial agonist at αβδ isoforms, which may render them particularly sensitive to allosteric modulation. The remarkable increase in gating efficacy of α1β3δ receptors suggests that αβδ isoforms, and by inference tonic forms of inhibition, may be important targets for barbiturates.