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Pentobarbital Differentially Modulates 13 and 132L GABA_A Receptor Currents

Departments of Neurology (H.-J.F., M.T.B., R.L.M.), Molecular Physiology and Biophysics (R.L.M.), and Pharmacology (R.L.M.), Vanderbilt University, Nashville, Tennessee

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 perisynaptic) inhibition, are unknown. Using ultrafast 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, whereas 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.

Received for publication May 11, 2004.

Accepted for publication July 8, 2004.

Address correspondence to: Dr. Robert L. Macdonald, Department of Neurology, 6140 MRB III, Vanderbilt University Medical Center, 465 21st Ave., South, Nashville, TN. E-mail: robert.macdonald{at}vanderbilt.edu

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