Chronic agonist exposure induces down-regulation and allosteric uncoupling of the gamma-aminobutyric acid/benzodiazepine receptor complex.

Article date: 1990/1/1

PubMed ID: 2153908

Journal name: Molecular pharmacology (ISSN: 0026-895X)


Using [3H]flunitrazepam as a probe for the benzodiazepine-sensitive modulator site located on the gamma-aminobutyric acid (GABA)A receptor complex, we have investigated the cellular regulation of the GABAA receptor in neuronal cultures derived from embryonic chick brain. Treatment of cultures with 1 mM GABA for 48 hr causes a reversible 35% decrease in the number of [3H]flunitrazepam binding sites with no change in affinity. The EC50 for chronic GABA-induced down-regulation is 94 microM and the half-time is 25 hr. The effect of GABA is blocked by SR-95531, a GABAA receptor antagonist, and mimicked by muscimol but not baclofen. Consistent with the decrease in [3H]flunitrazepam binding, chronic GABA exposure causes a 43% decrease in the binding of [35S]t-butylbicyclophosphorothionate, a ligand for the receptor-associated chloride ionophore. In addition to chronic GABA-induced down-regulation, allosteric interactions between GABA and benzodiazepine recognition sites are uncoupled by 34%. The half-time and pharmacology for chronic GABA-induced uncoupling is indistinguishable from that for GABA-induced down-regulation, consistent with the hypothesis that the action of GABA at a common site induces both down-regulation and uncoupling.

Author List: Roca D J, Rozenberg I, Farrant M, Farb D H

Publication Types: Journal Article; Research Support, U.S. Gov't, P.H.S.

Substances mentioned in the article: Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Pyridazines; Receptors, GABA-A; Muscimol; gamma-Aminobutyric Acid; Flunitrazepam; tert-butylbicyclophosphorothionate; gabazine;

Mesh terms: Allosteric Regulation; Animals; Brain/cytology; Bridged Bicyclo Compounds/metabolism; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Chick Embryo; Down-Regulation; Flunitrazepam/metabolism; In Vitro Techniques; Kinetics; Muscimol/pharmacology; Pyridazines/pharmacology; Receptors, GABA-A/drug effects; gamma-Aminobutyric Acid/administration & dosage;

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