Allopregnanolone acts as an inhibitory modulator on alpha1- and alpha6-containing GABA-A receptors.
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.
Hauser
C A
CA
Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
Wetzel
C H
CH
Rupprecht
R
R
Holsboer
F
F
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D058787:GABA-A Receptor Antagonists; D006801:Humans; D007031:Hypothalamus / Q000502:physiology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D009118:Muscimol / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011280:Pregnanolone / Q000494:pharmacology*; D011284:Pregnenolone / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D018118:Chloride Channels; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C018370:pregnenolone sulfate; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D011284:Pregnenolone; D011280:Pregnanolone