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First published on March 9, 2006; DOI: 10.1124/mol.106.022863

0026-895X/06/6906-1779-1782$20.00
Mol Pharmacol 69:1779-1782, 2006

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Accelerated Communication

Enantiomers of Neuroactive Steroids Support a Specific Interaction with the GABA-C Receptor as the Mechanism of Steroid Action

Wenjun Li, Douglas F. Covey, Juha-Matti Alakoskela, Paavo K. J. Kinnunen, and Joe Henry Steinbach

Departments of Anesthesiology (W.L., J.H.S.) and Molecular Biology and Pharmacology (D.F.C.), Washington University School of Medicine, St. Louis, Missouri; and Helsinki Biophysics and Biomembrane Group, Institute of Biomedicine/Biochemistry, University of Helsinki, Finland (J.-M.A., P.K.J.K.)

Neuroactive steroids can either potentiate or inhibit a variety of membrane channels. Most studies have suggested that the effects are mediated by specific association of the steroid with the affected channel. However, a recent study of the {rho}1 (GABA-C) receptor (Mol Pharmacol 66:56-69, 2004) concluded that the actions were consistent with an action of the steroid in the lipid bilayer to alter the lateral pressure profile in the membrane. The enantiomers of an optically active compound are expected to have identical physical properties, including interactions with hydrophobic portions of the cell membrane. We have used two pairs of enantiomers (pregnanolone and ent-pregnanolone, allopregnanolone and ent-allopregnanolone) and show that the ability to potentiate (allopregnanolone) or inhibit (pregnanolone) the {rho}1 receptor is enantioselective. Therefore, these results strongly suggest that the actions of these neuroactive steroids are mediated by interactions with chiral regions of the target protein, rather than by a change in membrane properties (including lateral pressure).

Received January 23, 2006; accepted March 9, 2006

Address correspondence to: Joe Henry Steinbach, Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail: jhs{at}wustl.edu




This article has been cited by other articles:


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W. Li, X. Jin, D. F. Covey, and J. H. Steinbach
Neuroactive Steroids and Human Recombinant {rho}1 GABA Receptors
J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 236 - 247.
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P. Li, J. Bracamontes, B. W. Katona, D. F. Covey, J. H. Steinbach, and G. Akk
Natural and Enantiomeric Etiocholanolone Interact with Distinct Sites on the Rat {alpha}1beta2{gamma}2L GABAA Receptor
Mol. Pharmacol., June 1, 2007; 71(6): 1582 - 1590.
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