The major class of inhibitory neurotransmitter receptors, the GABAA receptors, are modulated by a range of depressant drugs (eg benzodiazepines, ethanol) and their dysfunction has been associated with several neurological disorders. Recently, cDNA cloning has revealed the existence of numerous receptor subunit types. However, in the absence of genomic clones, it has been difficult to establish any link between inappropriate receptor expression and the implicated disease states. In addition, nothing is known of how expression of subunit genes is regulated in a coordinated and localized manner. As an initial step towards addressing these problems, we have isolated and sequenced human genomic clones encoding GABAA receptor subunits. The complete intron/exon structure and a large region of upstream sequence was determined for the beta1 subunit gene. The beta1 subunit protein is encoded by a relatively large gene (>75 kb), comprised of nine small exons. The beta1 gene has no structural similarity to the genes encoding the nicotinic acetylcholine receptors, a related family of receptor proteins. However, exons derived from a gene encoding the beta3 subunit indicate that intron/exon boundaries are conserved precisely between subtypes of subunits. Using the genomic clones as probes, the beta1 and beta3 subunits have been assigned to chromosomes 4 and 15, respectively. Ongoing studies will use the genomic clones to probe for restriction fragment length polymorphisms (RFLPs) in families displaying inherited neurological disorders (eg alcoholism, schizophrenia). In addition, the upstream regions of the beta1 gene will be characterized in order to understand how expression of the gene is regulated in neural tissues.
