THE ‘ABC’ OF GABA RECEPTORS: A BRIEF REVIEW

SUMMARY 1. In the mammalian central nervous system, GABA is the main inhibitory neurotransmitter. GABA is a highly flexible molecule and, thus, can exist in many low‐energy conformations. Conformationally restricted analogues of GABA have been used to help identify three major GABA receptors, termed GABA A , GABA B and GABA C receptors. 2. GABA A and GABA C receptors are members of a superfamily of transmitter‐gated ion channels that include nicotinic acetylcholine, strychnine‐sensitive glycine and 5HT 3 receptors. GABA A receptors are hetero‐oligomeric Cl – channels that are selectively blocked by the alkaloid bicuculline and modulated by steroids, barbiturates and benzodiazepines. To date, 16 human GABA A receptor cDNA have been cloned. 3. GABA B receptors are seven transmembrane receptors that are coupled to G‐proteins and activate second messenger systems and Ca 2+ and K + ion channels. To date, three GABA B receptor proteins have been cloned and these resemble metabotropic glutamate receptors. GABA B receptors are hetero‐oligomeric receptors made up of a mixture of a combination of the subunits. These receptors are selectively activated by (–)‐baclofen and CCGP27492 and are blocked by phaclofen, the phosphonic acid analogue of baclofen. 4. In contrast, GABA C receptors represent a relatively simple form of transmitter‐gated Cl – channel made up of a single type of protein subunit. Two human GABA C receptor cDNA have been cloned. These receptors are not blocked by bicuculline nor are they modulated by steroids, barbiturates or benzodiazepines. Instead, GABA C receptors are selectively activated by the conformationally restricted analogues of GABA in the folded conformation cis ‐4‐aminocrotonic acid and (1 S ,2 R )‐2‐(aminomethyl)‐1‐carboxycyclopropane. (1,2,5,6‐Tetrahydropyridine‐4‐yl)methylphosphinic acid, a methylphosphinic acid analogue of GABA in a partially folded conformation, is a selective antagonist at GABA C receptors.