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Abstract:
AB THE GABAA/benzodiazepine receptor is the principal inhibitory neurotransmitter receptor in the mammalian brain and is assembled from sequence-related subunits, such as [alpha]1[beta]2[gamma]2* In contrast to [alpha]1[beta]2[gamma]2 receptors, [alpha]6[beta]2[gamma]2 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 ([alpha]1His100 and [alpha]6Arg101). We now show by patch clamp analysis that this amino acid exchange also determines the diazepam potentiation. Thus, [alpha]1(Arg101)[beta]2[gamma]2 receptors do not, but [alpha]6(His100)[beta]2[gamma]2 receptors do exhibit diazepam potentiation. However, the same extracellular determinant is not responsible for the increased GABA sensitivity of [alpha]6[beta]2[gamma]2 receptors relative to [alpha]1[beta]2[gamma]2 receptors as revealed by electrophysiological analysis and by differential GABA sensitivity of [35S]TBPS binding. (C) Lippincott-Raven Publishers.
