Abstract
Background The g-aminobutyric acid type A (GABAA) receptors are the major inhibitory neurotransmitter receptors of the central nervous system. Benzodiazepine (Bz)-site ligands bind at the a/g interface and can enhance GABA-induced Cl currents. The efficacy of certain benzodiazepines strongly depends on the type of a(1,2,3,5) subunits in the receptors. Functionally selective compounds for a2/3 can be anxiolytic without having the side effect of sedation. The molecular basis for functional selectivity is investigated in this work.
Highlights
The g-aminobutyric acid type A (GABAA) receptors are the major inhibitory neurotransmitter receptors of the central nervous system
Two-electrode voltage-clamp electrophysiology recordings were performed in wild-type and mutated receptors expressed in Xenopus laevis oocytes
A sequence comparison between the a1 and a3 subunit revealed the residue R228 as unique for the a3 subunit among all a subunits. a3R228Amutated receptors completely lost their ability to respond to flumazenil
Summary
The g-aminobutyric acid type A (GABAA) receptors are the major inhibitory neurotransmitter receptors of the central nervous system. Benzodiazepine (Bz)-site ligands bind at the a/g interface and can enhance GABA-induced Cl− currents. The efficacy of certain benzodiazepines strongly depends on the type of a(1,2,3,5) subunits in the receptors. Selective compounds for a2/3 can be anxiolytic without having the side effect of sedation. The molecular basis for functional selectivity is investigated in this work. Binding mode of flumazenil in a1 and a3-containing receptors is very similar
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