GABA-dependent modulation of the Cl − ionophore by steroids in rat brain

Steroids inhibit the binding of [ 35S]t-butylbicyclophosphorothionate ([ 35S]TBPS) to the GABA A-benzodiazepine receptor (GBR) linked Cl − ionophore in a GABA dependent manner but not through the GABA A receptor. The most potent steroid evaluated is a naturally occuring metabolite of progesterone, 3 α-hydroxy,5 α-dihydroprogesterone with an IC 50 of ≈ 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.