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Correlation between gamma-aminobutyric acidA receptor ligand-induced changes in t-butylbicyclophosphoro[35S]thionate binding and 36Cl- uptake in rat cerebrocortical membranes.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 1991 Mar; Vol. 39 (3), pp. 394-8. - Publication Year :
- 1991
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Abstract
- We have explored the functional significance of various drug-induced changes in t-[35S]butylbycyclophosporothionate (TBPS) binding to gamma-aminobutyric acidA (GABAA) receptors by comparing them with the actions of the drugs on GABA-induced 36Cl- uptake in rat cerebrocortical membrane preparations. In the presence of micromolar concentrations of GABA, various benzodiazepine receptor agonists, 3 alpha-21-dihydroxy-5 alpha-pregnan-20-one, and pentobarbital inhibited [35S]TBPS binding, whereas ethyl-beta-carboline-3carboxylate (beta-CCE), an inverse agonist, stimulated it, in general agreement with earlier reports [Mol. Pharmacol. 23:326-336 (1983); Mol. Pharmacol. 30:218-225 (1986)]. The drug-induced changes in [35S]TBPS binding, after normalization with respect to the corresponding action of diazepam, were closely related to the relative ability of the drugs to affect 36Cl- uptake, with a correlation coefficient of 0.98 and a slope of 0.85. Upon abolishment of GABA action by the use of bicuculline, however, all the tested drugs stimulated [35S]TBPS binding to various degrees, and their relative changes displayed a lower correlation coefficient of 0.69, with a slope of 2. In particular, the effects of the anesthetic steroid and pentobarbital on [35S]TBPS binding were markedly altered by GABA, which at 2 microM increased not only their maximal effects, but also their half-maximal concentrations severalfold. On the other hand, GABA did not significantly affect these parameters for diazepam under our experimental conditions. Also, the GABA-independent changes in [35S]TBPS binding produced by various benzodiazepine receptor agonists matched reasonably well the actions of the drugs on 36Cl- uptake, with a correlation coefficient of 0.85 and a slope of 1.0. These data suggest more pronounced functional coupling of the GABA sites with those for the steroid and the barbiturate, as compared with the benzodiazepine site. It appears that the degree of [35S]TBPS binding in the presence of GABA closely reflects the functional state of GABAA receptors and may be useful for characterization of allosteric interactions between various sites on the receptors.
- Subjects :
- Animals
Bicuculline pharmacology
Carbolines pharmacology
Chloride Channels
Desoxycorticosterone analogs & derivatives
Desoxycorticosterone pharmacology
Diazepam pharmacology
Ethanol pharmacology
Flumazenil pharmacology
In Vitro Techniques
Ligands
Membrane Proteins drug effects
Membrane Proteins metabolism
Pentobarbital pharmacology
Pregnanolone analogs & derivatives
Pregnanolone pharmacology
Rats
Receptors, GABA-A drug effects
Synaptosomes metabolism
Bridged Bicyclo Compounds metabolism
Bridged Bicyclo Compounds, Heterocyclic
Cerebral Cortex metabolism
Chlorides metabolism
Receptors, GABA-A metabolism
gamma-Aminobutyric Acid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0026-895X
- Volume :
- 39
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 1848661