Alcohol Dependence and Genes Encoding α2 and γ1 GABAA Receptor Subunits: Insights from Humans and Mice

Abstract

One approach to identifying the causes of alcoholism, particularly without crossing ethical boundaries in human subjects, is to look at the person's genome (and particularly at the variations that naturally arise in the DNA) to identify those variations that seem to be found more commonly in people with the disease. Some of these analyses have focused on the genes that encode subunits of the receptor for the brain chemical (i.e., neurotransmitter) γ-aminobutyric acid (GABA). Different epidemiological genetic studies have provided evidence that variations in certain GABAA receptor (GABAA-R) subunits, particularly subunits α2 and γ1, are correlated with alcohol dependence. Manipulations of these genes and their expression in mice and rats also are offering clues as to the role of specific GABAA-Rs in the molecular mechanisms underlying alcoholism and suggest possibilities for new therapeutic approaches.

Segment of a single strand of DNA representing a fragment of the coding region from the GABRA2 gene from two different people. There are two SNPs in this gene region—one in which both variants of the DNA encode the same amino acid (i.e., a silent mutation) and one in which the two variants of the DNA encode different amino acids (i.e., a missense mutation).

Figure

Schematic representation of the cluster of GABA_A receptor genes on chromosome 4. Arrows indicate gene position, size, and direction of transcription. The subunits and the names of the corresponding genes are α2 (GABRA2), α4 (GABRA4), β1 (GABRB1), and γ1 (GABRG1).