GABA-dependent modulation of the Cl- ionophore by steroids in rat brain.
Steroids inhibit the binding of [35S]t-butylbicyclophosphorothionate ([ 35S]TBPS) to the GABAA-benzodiazepine receptor (GBR) linked Cl- ionophore in a GABA dependent manner but not through the GABAA receptor. The most potent steroid evaluated is a naturally occurring metabolite of progesterone, 3 alpha-hydroxy,5 alpha-dihydroprogesterone with an IC50 of approximately 17 nM. Structural requirements necessary for inhibitory activity coincide with those reported for anticonvulsant and anesthetic actions. Coupled with earlier evidence that these steroids do not act directly at the benzodiazepine receptor nor the [35S]TBPS labeled site to modulate the Cl- ionophore, the possibility is proposed that a distinct membrane-bound 'steroid site' coupled to the GBR-Cl- ionophore complex exists.
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides / Q000378:metabolism*; D002784:Cholesterol / Q000494:pharmacology; D066298:In Vitro Techniques; D007476:Ionophores / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013256:Steroids / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D007476:Ionophores; D013256:Steroids; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate; D002784:Cholesterol