GABA A receptor: Positive and negative allosteric modulators.

gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically, myriad existing nervous system drugs act as positive and negative allosteric modulators of these proteins, making GABA a major component of modern neuropharmacology, and suggesting that many potential drugs will be found that share these targets. Although some of these drugs act on proteins involved in synthesis, degradation, and membrane transport of GABA, the GABA receptors Type A (GABAA R) and Type B (GABAB R) are the targets of the great majority of GABAergic drugs. This discovery is due in no small part to Professor Norman Bowery. Whereas the topic of GABAB R is appropriately emphasized in this special issue, Norman Bowery also made many insights into GABAA R pharmacology, the topic of this article. GABAA R are members of the ligand-gated ion channel receptor superfamily, a chloride channel family of a dozen or more heteropentameric subtypes containing 19 possible different subunits. These subtypes show different brain regional and subcellular localization, age-dependent expression, and potential for plastic changes with experience including drug exposure. Not only are GABAA R the targets of agonist depressants and antagonist convulsants, but most GABAA R drugs act at other (allosteric) binding sites on the GABAA R proteins. Some anxiolytic and sedative drugs, like benzodiazepine and related drugs, act on GABAA R subtype-dependent extracellular domain sites. General anesthetics including alcohols and neurosteroids act at GABAA R subunit-interface trans-membrane sites. Ethanol at high anesthetic doses acts on GABAA R subtype-dependent trans-membrane domain sites. Ethanol at low intoxicating doses acts at GABAA R subtype-dependent extracellular domain sites. Thus GABAA R subtypes possess pharmacologically specific receptor binding sites for a large group of different chemical classes of clinically important neuropharmacological agents. This article is part of the "Special Issue Dedicated to Norman G. Bowery".