γ-Aminobutyric acid A receptor subunit mutant mice: new perspectives on alcohol actions
Section snippets
α1-Subunit
The α1-receptor subunit of the GABAA receptor is the most widely distributed α-subunit, having expression in the olfactory bulb, cortex, thalamus, hypothalamus, hippocampus, amygdala, midbrain, and cerebellum [4].
Three different groups have developed mutant mice possessing genetically altered α1-receptor subunits. Rudolph et al. [2] were the first to report knock-in mice possessing a point mutation (H101R) that eliminated diazepam-potentiation of GABA currents in vitro, and a second group
β2-Subunit
β2-Subunits are the most abundant of the beta subunits, and GABAA receptors containing them are found in virtually all brain structures, including olfactory bulb, cortex, hippocampus, thalamus, hypothalamus, amygdala, cerebellum, and midbrain [4]. Given this wide distribution, one would predict that β2-subunits are important for normal GABAergic functioning, and that they may also be important mediators of ethanol's behavioral effects.
β2-Subunit knock-in mice possessing a point mutation
γ2-Subunit knock-out and transgenic mice
The γ2-subunit can be alternatively spliced, creating two different splice variants, the γ2S (short) and γ2L (long). The γ2L splice variant differs from its shorter relative because it posses eight additional amino acids in the third intracellular loop. Importantly, these additional amino acids contain a protein kinase C phosphorylation site, and work by Wafford et al. [54] suggested that these eight amino acids are required for ethanol-enhancement of GABAA receptors possessing the γ2-subunit.
δ-Subunit
δ-Receptor subunits are found in most brain structures, albeit with limited abundance [4]. The δ-subunit is more prevalant in cerebellar granule cells where its localization is almost exclusively extrasynaptic [60]. Interestingly, a recent study suggests that extrasynaptic δ-containing GABAA receptors are particularly sensitive to ethanol [25], [61]. Furthermore, recent work indicates that δ-containing GABAA receptors, especially those also composed of α4 and β, may be up-regulated during
GABAA receptor subunit-associated quantitative trait loci (QTL)
Another way to determine whether different GABAA receptor subunits alter specific ethanol-related behavioral phenotypes is to examine the available quantitative trait loci literature. Ethanol-related behaviors are complex traits. This means that many different genes influence genetic vulnerability to ethanol's behavioral actions. Over the past decade QTL analysis has emerged as a strategy for mapping the many chromosomal regions that contain genes influencing sensitivity to a number of
GABAA receptor subunit-associated gene expression patterns
A genetic difference in DNA sequence within the coding region of an underlying gene is one mechanism by which significant QTLs might influence their associated traits. Such a mechanism might alter the amino acid sequence of the subunit, thereby altering GABAA receptor function and changing behavioral sensitivity to ethanol. For example, a recent report identified a polymorphism in the γ2-subunit gene that predicts a difference in amino acid sequence between the C57BL6/J (B6) and DBA/2J (D2)
Conclusion
GABAA receptors are known to have a role in the modulation of a number of ethanol's behavioral actions. Evidence suggests that the subunit composition of individual GABAA receptors may determine behavioral sensitivity to ethanol [1]. Indeed, studies of subunit knock-out mice have yielded considerable insights into the subunit specificity of ethanol's behavioral actions. These studies complement experiments aimed at mapping chromosomal regions (QTLs) underlying behavioral sensitivity to ethanol.
Acknowledgments
The authors would like to thank Virginia Bleck and Elizabeth Osterndorff-Kahanek for their excellent technical assistance. These experiments were supported by NIAAA (AA07471, AA13520, AA06399, AA14455).
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