Auto-modulation of neuroactive steroids on GABA A receptors: A novel pharmacological effect

GABA A receptor function is modulated by various important drugs including neuroactive steroids that act on allosteric modulatory sites and can directly activate GABA A receptor channels at high concentrations. We used whole cell patch-clamp recordings and rapid applications of the neuroactive stero...

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Bibliographic Details
Published in:Neuropharmacology 2007-02, Vol.52 (2), p.672-683
Main Authors: Wegner, Florian, Rassler, Cornelia, Allgaier, Clemens, Strecker, Karl, Wohlfarth, Kai
Format: Article
Language:English
Subjects:
Alphaxalone
Auto-modulation
Cell Line
Dose-Response Relationship, Drug
Drug Interactions
Electrophysiology
Enzyme Inhibitors - pharmacology
GABA A receptor
GABA Agonists - pharmacology
gamma-Aminobutyric Acid - pharmacology
Gene Expression - drug effects
Humans
Isoxazoles - pharmacology
Membrane Potentials - drug effects
Membrane Potentials - physiology
Neuroactive steroid
Patch-Clamp Techniques - methods
Phosphorylation
Pregnanediones - pharmacology
Protein Subunits - genetics
Protein Subunits - metabolism
Receptors, GABA-A - genetics
Receptors, GABA-A - metabolism
Recombinant Proteins - metabolism
Steroids - pharmacology
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Summary:GABA A receptor function is modulated by various important drugs including neuroactive steroids that act on allosteric modulatory sites and can directly activate GABA A receptor channels at high concentrations. We used whole cell patch-clamp recordings and rapid applications of the neuroactive steroid alphaxalone to investigate repetitive steroid effects. Alphaxalone potentiation of submaximal GABA-evoked currents was enhanced significantly by repetitive coapplications at all investigated recombinant isoforms (α1β3δ, α1β3γ2L, α6β3δ, α6β3γ2L) and at GABA A receptors of differentiated human NT2 neurons. A similar increase of current amplitudes was induced by repetitive applications of a high steroid concentration without GABA. We refer to these reversible effects as auto-modulation because repeated interactions of steroids enhanced their own pharmacological impact at the receptor sites in a time and concentration dependent manner without affecting GABA controls. Pronounced auto-modulatory actions were also measured using the neurosteroid 5α-THDOC in contrast to indiplon, THIP, and pentobarbital indicating a steroid specificity. Protein kinase A inhibition significantly reduced alphaxalone auto-modulation at α1β3γ2L, α6β3γ2L, and α6β3δ subtypes while it enhanced potentiation at α1β3δ isoforms suggesting a crucial influence of receptor subunit composition and phosphorylation for steroid actions. Especially at extrasynaptic GABA A receptor sites containing the δ subunit steroid auto-modulation may have a critical role in enhancing potentiation of GABA-induced currents.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2006.09.009