Enantiomers of neuroactive steroids support a specific interaction with the GABA-C receptor as the mechanism of steroid action

Molecular Pharmacology
Wenjun LiJoe Henry Steinbach

Abstract

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 rho1 (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 rho1 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).

References

Jan 21, 2004·British Journal of Pharmacology·Juan D Goutman, Daniel J Calvo
Jun 11, 2004·Biophysical Journal·Justin Gullingsrud, Klaus Schulten
Jun 24, 2004·Molecular Pharmacology·Kendall D W Morris, Jahanshah Amin
Oct 6, 2005·European Biophysics Journal : EBJ·Michael Patra
Dec 16, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gustav AkkSteven Mennerick

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Citations

Jul 20, 2007·The Journal of Pharmacology and Experimental Therapeutics·Wenjun LiJoe Henry Steinbach
Dec 8, 2015·Steroids·El-Sayed Ibrahim El-DesokyAbdel-Aziz Mahmoud Dawidar
May 22, 2009·Journal of Neurochemistry·Juan Francisco CodocedoJuan Pablo Huidobro-Toro
Sep 2, 2006·Biochimica Et Biophysica Acta·Juha-Matti AlakoskelaPaavo K J Kinnunen
Sep 12, 2006·Trends in Cell Biology·P A Janmey, P K J Kinnunen
Jun 15, 2007·Pharmacology & Therapeutics·Alastair M HosieTrevor G Smart
May 23, 2009·Molecular BioSystems·Jianjun SuiWei Ning Chen
May 26, 2007·Pharmacology & Therapeutics·Gustav AkkSteven Mennerick

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