Avermectin B1a: an irreversible activator of the gamma-aminobutyric acid-benzodiazepine-chloride-ionophore receptor complex |
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Authors: | S M Paul P Skolnick M Zatz |
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Institution: | 1. Clinical Psychobiology Branch, National Institutes of Health, Bethesda, Maryland 20205 USA;2. Laboratory of Bioorganic Chemistry, NIAMDD, National Institutes of Health, Bethesda, Maryland 20205 USA;3. Laboratory of Clinical Science, NIMH, National Institutes of Health, Bethesda, Maryland 20205 USA |
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Abstract: | Avermectin B1a, an antihelminthic macrocyclic lactone, has been previously shown to reduce muscle membrane resistance by stimulating γ-aminobutyric acid-mediated chloride conductance. Since the benzodiazepine receptor is coupled to a receptor for γ-aminobutyric acid and related chloride ionophore, the effects of Avermectin B1a on 3H]diazepam binding to the benzodiazepine receptor were studied. In well-washed membrane fragments from rat cerebral cortex, Avermectin B1a markedly increased the binding of 3H]diazepam to benzodiazepine receptors. This effect was qualitatively similar to that observed with either γ-aminobutyric acid or chloride ion and was partially reversed by the γ-aminobutyric acid receptor antagonist, bicuculline. In contrast to the effects of γ-aminobutyric acid and chloride, the enhanced binding of 3H]benzodiazepine elicited by Avermectin B1a was reversed by extensive washing of the membrane preparation. Avermectin B1a appears to irreversibly modify benzodiazepine receptors at a γ-aminobutyric acid-chloride recognition site and may be valuable in biochemical studies of the regulation of benzodiazepine receptor function. |
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Keywords: | AVM GABA γ-aminobutyric acid CNS central nervous system |
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