TY - JOUR T1 - beta-Carboline gamma-aminobutyric acidA receptor inverse agonists modulate gamma-aminobutyric acid via the loreclezole binding site as well as the benzodiazepine site. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 965 LP - 969 VL - 48 IS - 6 AU - A Stevenson AU - P B Wingrove AU - P J Whiting AU - K A Wafford Y1 - 1995/12/01 UR - http://molpharm.aspetjournals.org/content/48/6/965.abstract N2 - The benzodiazepine site on the gamma-aminobutyric acid(A) (GABAA) receptor is the principle site of action for a number of structurally diverse compounds, including the beta-carbolines, many of which bind with high affinity. The apparent reversal of inhibition and potentiation by high concentrations of methyl-6,7-dimethoxy-4-ethyl-beta-carboline (DMCM) and other beta-carbolines has been reported by several groups and is insensitive to the benzodiazepine antagonist Ro 15-1788. By using alpha 6-containing receptors, which have low affinity for benzodiazepines, we observed robust potentiation of GABAA responses by micromolar concentrations of DMCM and other beta-carbolines that is dependent on the beta subunit variant. The beta subunit-dependent potentiation by the anticonvulsant loreclezole is dependent on a single amino acid in the putative transmembrane 2 region. By using single point mutations that discriminate the loreclezole site, we show that potentiation by DMCM is also dependent on the presence of the same amino acid, Asn290, in beta 2 or beta 3 (serine in beta 1), providing evidence that the low affinity site for beta-carboline potentiation is the loreclezole site. The potentiation is independent of the alpha subunit and is more pronounced on alpha 6-containing receptors due to the lack of DMCM inhibition via the benzodiazepine site. In addition, the potentiation observed is competitive with that of loreclezole, and other beta-carbolines, such as ethyl-beta-carboline-3-carboxylate and propyl-beta-carboline-3-carboxylate, act in a similar manner. The finding that beta-carbolines can act via the loreclezole site as well as the benzodiazepine site suggests that a wider variety of compounds may act via this site and shows that compounds can interact with more than one modulatory site on the GABAA receptor. ER -