Complex interactions between pregnenolone sulfate and the t-butylbicyclophosphorothionate-labeled chloride ionophore in rat brain.
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.
Gee
K W
KW
Division of Biological Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033.
Joy
D S
DS
Belelli
D
D
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism*; D004347:Drug Interactions; D007476:Ionophores / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D011284:Pregnenolone / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D018118:Chloride Channels; D002712:Chlorides; C062606:GABA-benzodiazepine receptor-chloride ionophore complex; D007476:Ionophores; D008565:Membrane Proteins; D011963:Receptors, GABA-A; C018370:pregnenolone sulfate; C037476:tert-butylbicyclophosphorothionate; D011284:Pregnenolone