Received for publication May 12, 2004.
Revised July 7, 2004.
Accepted for publication July 8, 2004.

PENTOBARBITAL DIFFERENTIALLY MODULATES 13 AND 132L GABA_A RECEPTOR CURRENTS

Abstract

GABA_A receptors are modulated by a variety of compounds including the neurosteroids and barbiturates. Although the effects of barbiturates on isoforms, thought to dominate phasic (synaptic) GABAergic inhibition, have been extensively studied, the effects of pentobarbital on kinetic properties of GABA_A receptors, thought to mediate tonic (extra or peri-synaptic) inhibition, are unknown. Utilizing ultra-fast drug delivery and single channel recording techniques, we demonstrate isoform specific pentobarbital modulation of low efficacy, minimally desensitizing 13 currents and high efficacy, rapidly desensitizing 132L currents. Specifically, with saturating concentrations of GABA, pentobarbital substantially potentiated peak 13 receptor currents but failed to potentiate peak 132L receptor currents. Also, pentobarbital had opposite effects on the desensitization of 13 (increased) and 132L (decreased) receptor currents evoked by saturating GABA. Pentobarbital increased steady-state 13 receptor single channel open duration primarily by introducing a longer-duration open state, while for 132L 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 isoforms, which may render them particularly sensitive to allosteric modulation. The remarkable increase in gating efficacy of 13 receptors suggests that isoforms, and by inference tonic forms of inhibition, may be important targets for barbiturates.

Key words: GABAA, GABAC, Single channel kinetics, Barbiturates

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