Gamma-aminobutyric acidA receptor complexes in rat frontal cortex and spinal cord show differential responses to steroid modulation.
Regional differences in neuroactive steroid modulation of the gamma-aminobutyric acidA receptor-chloride ionophore complex (GBRC), as measured by t-butylbicyclophosphoro[35S]thionate ([35S] TBPS) binding and 36Cl- uptake, were demonstrated in rat spinal cord versus frontal cortex. The rank order of potencies of a series of 5 alpha- and 5 beta-reduced isomers of 3 alpha-hydroxylated steroids against [35S]TBPS binding were different between regions. The differences in rank order of potencies imply the possible existence of heterogeneous populations of GBRC-coupled steroid recognition sites. The relative potencies of selected 5 alpha- and 5 beta-reduced isomers as potentiators of 36Cl- uptake paralleled their potencies as inhibitors of [35S]TBPS binding. Differential sensitivity of the steroid recognition site to the allosteric influence of gamma-aminobutyric acid was also demonstrated. It appears that regionally specific responses to GBRC-active steroids do occur, although the functional consequences of these effects await evaluation in appropriate in vivo models.
Gee
K W
KW
Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles 90033.
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D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002712:Chlorides / Q000378:metabolism / Q000493:pharmacokinetics; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D007476:Ionophores / Q000378:metabolism; D008297:Male; D010424:Pentobarbital / Q000494:pharmacology; D011276:Pregnanediol / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013256:Steroids / Q000494:pharmacology*; D013462:Sulfur Radioisotopes; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; C062606:GABA-benzodiazepine receptor-chloride ionophore complex; D007476:Ionophores; D011963:Receptors, GABA-A; D013256:Steroids; D013462:Sulfur Radioisotopes; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone; D010424:Pentobarbital; D011276:Pregnanediol; D003975:Diazepam