Pharmacology of recombinant γ‐aminobutyric acidA receptors rendered diazepam‐insensitive by point‐mutated α‐subunits

Abstract

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^H105R) results not only in diazepam-insensitivity of the respective αxβ2,3γ2-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.