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

Amino acids in the α- and γ-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 (α1(H101R), α2(H101R), α3(H126R), and α5(H1015R) results not only in diazepam-insensitivity of the respective αxβ2,γ2-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 wild-type 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.