Enantioselectivity at the physiologically active GABAA receptor

A subfraction of cortical tissue from rat brain, containing membrane vesicles was prepared freshly with added protease inhibitors and antioxidant. The preparation was used to measure stimulation of transmembrane 36C1- flux and inhibition of bicuculline-sensitive [3H] muscimol binding by (+)-(S) and (-)-(R) enantiomers of dihydromuscimol at 30 degrees in physiological salt solution. Displacement of bound [3H]muscimol and stimulation of 36Cl- flux appeared in the 0.1-10 microM concentration range of the enantiomers, channel gating, however, required rather high concentrations. Degrees of enantioselectivity for channel gating, desensitization of and binding to GABAA receptors were estimated by the concentration ratios of dihydromuscimol enantiomers, [(-)-(R)]/[(+)-(S)], at the same level of response or displacement. Different enantioselectives were observed for channel gating (6 +/- 3), receptor binding (3 +/- 2) and desensitization (no selectivity). The low and concentration-dependent enantioselectives found for channel gating and receptor binding can be explained by desensitization and heterogeneity of GABAA receptors.