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

Abstract

The inhibitory tone maintained throughout the central nervous system relies predominantly on the activity of neuronal GABAA (gamma-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 gamma2 subunit and are sensitive to modulation by BZs (benzodiazepines), but differ with regard to alpha and beta 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 alpha 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 beta 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.

Preliminary array analysis reveals novel genes regulated by ovarian steroids in the monkey raphe region

“…The α3 subunit contributes to the benzodiazepine binding site, which also binds to P metabolites (Biggio et al 2001;Lambert et al 2003;Rupprecht 2003;Wafford et al 2004). Thus, P, through a genomic mechanism could facilitate nongenomic mechanisms of action by increasing the receptor that binds to its metabolites.…”

Evidence for a Significant Role of α3-Containing GABAAReceptors in Mediating the Anxiolytic Effects of Benzodiazepines

“…However, the differential effects of pharmacologically induced changes in activity in wild-type and transgenic mice can confound the interpretation of locomotor-based experiments (Reynolds et al, 2001;Crestani et al, 2001). Because this differential locomotor effect is also observed with ␣2H101R mice (Wafford et al, 2004), we examined the effects of TP003 and the nonselective agonist CDP using the physiological SIH model. The SIH is an integral part of an individual's response to the perception of a distressing situation (Marazziti et al, 1992) and, as a manifestation of autonomic hyperactivity, is one of the diagnostic items of generalized anxiety mentioned in DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition).…”

“…Diazepam-induced anxiolysis appeared absent in mice with the ␣2H101R point mutation but present in mice with the ␣3H126R point mutation compared with wild-type controls when assessed using two locomotor-dependent tests: light-dark choice and elevated plus maze (Löw et al, 2000). However, because ␣2H101R mice are more sensitive to the locomotor impairing effects of diazepam than wild-type controls (Wafford et al, 2004), there remains some controversy as to whether the lack of an anxiolytic-like effect in ␣2H101R mice might be more related to hypoactivity than anxiolysis per se Reynolds et al, 2001).…”

Heterogeneity of GABAA Receptors: Revived Interest in the Development of Subtype-selective Drugs

“…Because diazepam still acts on receptor subtypes containing the α1, α3, and α5 subunits in α2(His101Arg) mice, the experiments do not necessarily predict whether, e.g an α3-or α5-selective agonist may also display an anxiolytic-like action in the various anxiolytic tests. In addition, since most of the anxiolytic tests for mice rely on locomotor activity, marked changes in activity between two groups of mice can confound the interpretation of data and can lead to discrepant interpretations derived from different behavioural tests [172].…”