Differentiating the role of γ -aminobutyric acid type A (GABAA) receptor subtypes

The inhibitory tone maintained throughout the central nervous system relies predominantly on the activity of neuronal GABAA (γ -aminobutyric acid type A) receptors. This receptor family comprises various subtypes that have unique regional distributions, but little is known about the role played by each subtype. The majority of the receptors contain a γ 2 subunit and are sensitive to modulation by BZs (benzodiazepines), but differ with regard to α and β subunits. Mutagenesis studies combined with molecular modelling have enabled a greater understanding of receptor structure and dynamics. This can now be extended to in vivo activity through translation to genetically modified mice containing these mutations. Ideally, the mutation should leave normal receptor function intact, and this is the case with mutations affecting the BZ-binding site of the GABAA receptor. We have generated mutations, which affect the BZ site of different α subunits, to enable discrimination of the various behavioural consequences of BZ drug action. This has aided our understanding of the roles played by individual GABAA receptor subtypes in particular behaviours. We have also used this technique to explore the role of different β subunits in conferring the anaesthetic activity of etomidate. This technique together with the development of subtype-selective compounds facilitates our understanding of the roles played by each receptor subtype. Introduction GABAA (γ -aminobutyric acid type A) receptors are a major member of the ligand-gated ion-channel family and are the primary means for exerting inhibitory control throughout the central and peripheral nervous systems. A great deal is now known about the molecular composition of these receptors and how the distinct subtypes are constructed from a family of 18 different subunits to form the characteristic pentameric channel–protein complex with a central chlorideselective pore [1–3]. Expression studies of different subunit combinations have clearly defined some of the pharmacological differences between specific receptor combinations that are thought to be expressed in vivo, and we now have a clearer understanding of at least some of those amino acid residues, which contribute to ligand-binding domains and channel function at the receptor level [4]. It is possible to utilize these pharmacological and physiological discoveries in combination with crystallographic data and molecular modelling to hypothesize the protein structure and physical domains for ligand interactions [5,6]. We can also combine these findings together with recombinant genetics to make single mutations or manipulations in targeted subunit proteins in mice, to study the in vivo consequences of alterations in specific subunits [7]. In the present study, we have used this technique to investigate the role played by individual