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The Journal of Neuroscience, November 26, 2003, 23(34):10934-10943

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Cellular/Molecular
Neurosteroids Shift Partial Agonist Activation of GABA_A Receptor Channels from Low- to High-Efficacy Gating Patterns

Matt T. Bianchi¹ and Robert L. Macdonald²

¹Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48104-1687, and ²Departments of Neurology, Molecular Physiology and Biophysics, and Pharmacology, Vanderbilt University, Nashville, Tennessee 37212

Although GABA activates synaptic () GABA_A receptors with high efficacy, partial agonist activation of isoforms and GABA activation of the primary extrasynaptic () GABA_A receptors are limited to low-efficacy activity, characterized by minimal desensitization and brief openings. The unusual sensitivity of receptor channels to neurosteroid modulation prompted investigation of whether this high sensitivity was dependent on the subunit or the low-efficacy channel function that it confers. We show that the isoform specificity ( > ) of neurosteroid modulation could be reversed by conditions that reversed isoform-specific activity modes, including the use of -alanine to achieve increased efficacy with receptors and taurine to render receptors low efficacy. We suggest that neurosteroids preferentially enhance low-efficacy GABA_A receptor activity independent of subunit composition. Allosteric conversion of partial to full agonism may be a general mechanism for reversibly scaling the efficacy of GABA_A receptors to endogenous partial agonists.

Key words: GABA_A receptor; neurosteroid; modal gating; desensitization; subunit; taurine; -alanine

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Received July 23, 2003; revised September 12, 2003; accepted September 22, 2003.

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