Group-selective reagent modification of the benzodiazepine-gamma- aminobutyric acid receptor-ionophore complex reveals that low-affinity gamma-aminobutyric acid receptors stimulate benzodiazepine binding

TP Burch, R Thyagarajan and MK Ticku

The modification of membrane proteins with diethylpyrocarbonate (DEP) and diazotized sulfanilate was investigated on the binding of three benzodiazepine radioligands in three brain regions. Both of these reagents produced a dose-dependent inactivation of [3H] diazepam, [3H]flunitrazepam, and [3H]propyl beta-carboline-3-carboxylate binding to cortex, cerebellum, and hippocampus. Both DEP and diazotized sulfanilate decrease the Bmax of the benzodiazepine binding sites without altering the KD. The ability of muscimol and pentobarbital to enhance [3H]diazepam binding was not altered by DEP pretreatment in any of the three regions. Scatchard analysis indicated that, following the inactivation of 40-50% of [3H]diazepam binding by 1 mM DEP, pentobarbital and muscimol were still able to increase the affinity of [3H]diazepam binding in cortex, cerebellum, and hippocampus. In contrast, diazotized sulfanilate pretreatment abolishes the ability of muscimol and pentobarbital to enhance [3H]diazepam binding in these three regions. The effects of these reagents on [3H] gamma-aminobutyric acid (GABA) binding revealed that sulfanilate but not DEP eliminates the low-affinity GABA receptor sites in cortex and cerebellum. Thus, while both DEP and sulfanilate inactivate benzodiazepine binding sites, only sulfanilate abolishes the low-affinity GABA binding sites and the ability of the GABA agonists to enhance [3H]diazepam binding. These results suggest that the stimulation of benzodiazepine binding appears to be mediated by the low-affinity GABA receptors.

Volume 23, Issue 1, pp. 52-59, 01/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics

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