John Tulinsky and Ronald B. Gammill* Pages 226 - 253 ( 28 )
The inhibitory neurotransmitter y-aminobutyrate (GA8A) elicits its physiological effects through interactions with two distinct classes of cell surface receptors in the central nervous system. The GA8AA receptor is a member of the superfamily of ligand-gate8 ion channels and is regulated allosterically at a number of distinct sites. The complex is a heterooligomeric integral membrane protein made up of a, p and y subunits. In addition to the site at which GA8A itself binds, radioligand binding studies have defined at least three other high-affinity binding sites on the receptor complex, the benzodiazepine receptor site, the picrotoxin site (which also recognizes cage-convulsants) and the barbiturate site. There is also evidence for an avermectin 81a site and a steroid site. The ligands which bind at the various sites on this complex are chemically quite diverse and mediate a wide variety of pharmacological actions and have a continuum of intrinsic activity ranging from full agonist (anxiolytic, hypnotic, and anticonvulsant agents) through antagonist to inverse agonists (proconvulsants and anxiogenic agents). The GA8A 8 receptor displays a neuronal distribution and pharmacology distinct from that of the GA8AA receptor. The GA8A 8 receptor is a metabotropic receptor which is associated with an inhibitor GTP-binding protein regulating adenylate cyclase, calcium and potassium channels. 8aclofen and phaclofen are selective agonist and antagonist for GA8A8. In this review we will present the most current thinking regarding the importance of the various receptor subtypes, the syntheses of the various ligands that modulate GA8AA and GA8A 8 receptors and their pharmacology.