Complex interactions between pregnenolone sulfate and the t-butylbicyclophosphorothionate-labeled chloride ionophore...

Detailed studies of the interactions between the 'neuroactive' steroid, pregnenolone sulfate (PS), and the gamma-aminobutyric acid (GABA)/benzodiazepine receptor-linked chloride ionophore (GBRC) labeled by [35S]t-butylbicyclophosphorothionate ([35S]TBPS) in the rat brain reveal a site of action allosteric to the TBPS-labeled site as demonstrated by the ability of PS to accelerate TBPS-initiated dissociation of [35S]TBPS. In contrast to previous findings, PS modulates [35S]TBPS binding in a GABA 'agonist'-like fashion with micromolar potencies. The role of PS in the regulation of neuronal excitability through the GBRC is questioned, based upon the observation that brain concentrations of PS are 2-3 orders of magnitude less than that necessary for the modulation of chloride conductance in vitro.