CURRENT POTENTIATION BY DIAZEPAM BUT NOT GABA SENSITIVITY IS DETERMINED BY A SINGLE HISTIDINE RESIDUE

THE GABA(A)/benzodiazepine receptor is the principal inhibitory neurotransmitter receptor in the mammalian brain and is assembled from sequence-related subunits, such as alpha1beta2gamma2. In contrast to alpha1beta2gamma2 receptors, alpha6beta2gamma2 receptors fail to exhibit high-affinity binding of allosteric positive modulators of GABA-activated chloride currents. The critical determinant responsible for this difference in ligand binding was previously traced to a position in the extracellular domain of the two alpha subunits (alpha1His100 and alpha6Arg101). We now show by patch clamp analysis that this amino acid exchange also determines the diazepam potentiation. Thus, alpha1(Arg101)beta2gamma2 receptors do not, but alpha6(His100)beta2gamma2 receptors do exhibit diazepam potentiation. However, the same extracellular determinant is not responsible for the increased GABA sensitivity of alpha6beta2gamma2 receptors relative to alpha1beta2gamma2 receptors as revealed by electrophysiological analysis and by differential GABA sensitivity of [S-35]TBPS binding.