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The Journal of Neuroscience, March 1, 2002, 22(5):1541-1549

Enhanced Neurosteroid Potentiation of Ternary GABA_A Receptors Containing the  Subunit

Kai M. Wohlfarth¹, Matt T. Bianchi², and Robert L. Macdonald^{3, 4, 5}

Department of ¹  Neurology and ²  Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48104-1687, and Departments of ³  Neurology, ⁴  Molecular Physiology and Biophysics, and ⁵  Pharmacology, Vanderbilt University, Nashville, Tennessee 37212

Attenuated behavioral sensitivity to neurosteroids has been reported for mice deficient in the GABA_A receptor  subunit. We therefore investigated potential subunit-specific neurosteroid pharmacology of the following GABA_A receptor isoforms in a transient expression system: 132L, 13, 632L, and 63. Potentiation of submaximal GABA_A receptor currents by the neurosteroid tetrahydrodeoxycorticosterone (THDOC) was greatest for the 13 isoform. Whole-cell GABA concentration-response curves performed with and without low concentrations (30 nM) of THDOC revealed enhanced peak GABA_A receptor currents for isoforms tested without affecting the GABA EC₅₀. 13 currents were enhanced the most (>150%), whereas the other isoform currents were enhanced 15-50%. At a higher concentration (1 µM), THDOC decreased peak 132L receptor current amplitude evoked by GABA (1 mM) concentration jumps and prolonged deactivation but had little effect on the rate or extent of apparent desensitization. Thus the polarity of THDOC modulation depended on GABA concentration for 132L GABA_A receptors. However, the same protocol applied to 13 receptors resulted in peak current enhancement by THDOC of >800% and prolonged deactivation. Interestingly, THDOC induced pronounced desensitization in the minimally desensitizing 13 receptors. Single channel recordings obtained from 13 receptors indicated that THDOC increased the channel opening duration, including the introduction of an additional longer duration open state. Our results suggest that the GABA_A receptor  subunit confers increased sensitivity to neurosteroid modulation and that the intrinsic gating and desensitization kinetics of 13 GABA_A receptors are altered by THDOC.

Key words: GABA_A receptor; subunit; neurosteroid; desensitization; single channel; gating

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2251541-09$05.00/0

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