Pharmacology of recombinant γ-aminobutyric acida receptors rendered diazepam-insensitive by point-mutated α-subunits

Amino acids in the alpha- and gamma-subunits contribute to the benzodiazepine binding site of GABA(A)-receptors. We show that the mutation of a conserved histidine residue in the N-terminal extracellular segment (alpha 1(H101R), alpha 2(H101R), alpha 3(H126R) and alpha 5(H105R)) results not only in diazepam-insensitivity of the respective alpha x beta 2,3 gamma 2-receptors but also in an increased potentiation of the GABA-induced currents by the partial agonist bretazenil, Furthermore, Ro 15-4513, an inverse agonist at wildtype receptors, acts as an agonist at all mutant receptors, This conserved molecular switch can be exploited to identify the pharmacological significance of specific GABA(A)-receptor subtypes in vivo. (C) 1998 Federation of European Biochemical Societies.