Steroid modulation of GABAA receptors in an amphibian brain.
Steroids can modulate gamma-aminobutyric acid (GABAA) receptor function in rat brains, but the physiological relevance of this mechanism is still unclear. To determine whether this phenomenon is widespread among vertebrates, we investigated steroid modulation of GABAA receptors in amphibian brain tissue. Equilibrium binding parameters for t-butylbicyclophosphorothionate ([35S]TBPS) and [3H]flunitrazepam were similar in Taricha granulosa and mammalian brains, as was the allosteric regulation of [35S]TBPS and [3H]flunitrazepam binding by GABA. The rank order and absolute potencies of steroids to inhibit [35S]TBPS binding and enhance [3H]flunitrazepam binding were also similar in Taricha and rat brains. As in mammalian studies, physiological concentrations of corticosterone had no effect on ligand binding or GABA-stimulated Cl- uptake. In autoradiographic studies, 3 alpha-hydroxy-5 alpha-pregnan-20-one inhibited [35S]TBPS binding sites in all brain regions examined, whereas corticosterone had no effect on [35S]TBPS binding. These studies suggest that the steroid recognition sites on GABAA receptors have been highly conserved through vertebrate evolution and thus portend physiologically important functions. However, the pharmacological profiles for the GABAA receptor and the high-affinity corticosteroid receptor are apparently different, suggesting there are multiple types of steroid recognition sites on neuronal membranes.
Orchinik
M
M
Department of Zoology, Oregon State University, Corvallis 97331.
Murray
T F
TF
Moore
F L
FL
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002462:Cell Membrane / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008322:Mammals; D009474:Neurons / Q000378:metabolism*; D011280:Pregnanolone / Q000494:pharmacology; D011284:Pregnenolone / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012455:Salamandridae; D013045:Species Specificity; D013256:Steroids / Q000494:pharmacology*; D013462:Sulfur Radioisotopes; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D003292:Convulsants; D011963:Receptors, GABA-A; D013256:Steroids; D013462:Sulfur Radioisotopes; C018370:pregnenolone sulfate; D014316:Tritium; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; D011284:Pregnenolone; D011280:Pregnanolone; D003345:Corticosterone