Molecular biology of GABA _A receptors

Abstract

The major type of receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), called the GABAA receptor, is a member of a gene superfamily of ligand-gated ion channels. This receptor is a hetero-oligomeric protein composed of several distinct polypeptide types (alpha, beta, gamma, and delta). Molecular cloning of these polypeptides reveals that they show 20-40% identity with each other, and 10-20% identity with polypeptides of the nicotinic acetylcholine receptors and strychnine-sensitive glycine receptor. Each polypeptide type is also represented by a family of genes whose members have 60-80% amino acid sequence identity. Regions of conserved and variable amino acid sequence suggest structural and functional domains within each polypeptide. All of the polypeptides when expressed in heterologous cells produce GABA-activated chloride channels, and the different subtypes express different pharmacological properties. The distributions of mRNAs for the different GABAA receptor polypeptides and their subtypes show significant brain regional variation consistent with pharmacological and biochemical evidence for receptor heterogeneity. Subpopulations of GABAA receptors with different cellular and regional locations show differential sensitivity to GABA, to modulators like steroids, to physiological regulation, to disease processes, and to pharmacological manipulation by drugs such as benzodiazepines. The properties of the different subpopulations of GABAA receptors are determined by which one or more of the different polypeptides and their subtypes are expressed in a given cell to produce a variety of different oligomeric protein structures. Molecular cloning techniques have produced rapid advances in understanding the GABAA receptor protein family.