Abstract
Allopregnanolone, known so far to act as a gamma-aminobutyric acid (GABA) agonist, allosterically decreased the affinity of the GABA agonist muscimol for recombinant alpha1beta2gamma2 and alpha6beta2gamma2 GABA-A receptors. Pregnenolone sulfate, a GABA antagonist, had a similar effect. Both of these neuroactive steroids also reduced the time constant of desensitization (tau) of GABA-induced chloride currents. The effect on desensitization was demonstrated for native receptors of hypothalamic neurons as well as for the recombinant GABA-A receptors. Hence neuroactive steroids may differentially modulate distinct assemblies of GABA-A receptors and thus induce a more subtle modulation of GABAergic synaptic transmission than previously thought possible.
MeSH terms
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Animals
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Anti-Anxiety Agents / pharmacology*
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Cell Line
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Cell Membrane / metabolism
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Chloride Channels / drug effects
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Chloride Channels / physiology
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GABA-A Receptor Antagonists*
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Humans
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Hypothalamus / physiology
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Kinetics
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Molecular Sequence Data
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Muscimol / metabolism
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Neurons / drug effects
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Neurons / physiology*
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Patch-Clamp Techniques
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Pregnanolone / pharmacology*
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Pregnenolone / pharmacology
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Rats
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Receptors, GABA-A / chemistry
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Receptors, GABA-A / physiology
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Transfection
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gamma-Aminobutyric Acid / pharmacology*
Substances
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Anti-Anxiety Agents
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Chloride Channels
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GABA-A Receptor Antagonists
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Receptors, GABA-A
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Recombinant Proteins
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pregnenolone sulfate
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Muscimol
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gamma-Aminobutyric Acid
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Pregnenolone
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Pregnanolone