Nervous System Membrane Proteins Heterogeneity of GABA,-benzodiazepine receptors

Introduction The GABAA receptor of mammalian brain is a ligand-gated chloride ion channel and the site of action of a variety of pharmacologically and clinically important drugs. Thus, electrophysiological experiments in many different systems have indicated that the anxiolytic, anticonvulsant, muscle relaxant and sedative hypnotic benzodiazepines like diazepam or flunitrazepam enhance and some anxiogenic P-carbolines reduce the action of GABA at the GABA, receptors [l, 21. Similarly, some depressant barbiturates, the general anaesthetic and anticonvulsant etomidate, the pyrazolopyridine etazolate and some steroids have been reported to enhance the membrane effects of endogenous or exogenous GABA [ 1,2]. Biochemical experiments indicated the existence of specific high-affinity binding sites for benzodiazepines which seem to be closely associated with GABA, receptors [ 11. Since the affinity of benzodiazepines for these binding sites is highly correlated with the clinical potency of these drugs, it was concluded that these specific high-affinity binding sites are the receptors by which the benzodiazepines exert their pharmacologically and clinically relevant actions. The close association of benzodiazepine and GABA, receptors and the modulation by benzodiazepines of the membrane effects of GARA indicates that benzodiazepine receptors are allosteric modulatory sites on GABA, receptors [ 1, 21. Additional modulatory sites for barbiturates, some clinically active pyrazolopyridines, for avermectin B,a, some steroids and for some convulsant cage compounds have been identified on GABA, receptors using binding studies [2]. All these binding sites allosterically interact with each other, and it is now clear that the GABAAbenzodiazepine receptor is a highly regulated complex molecular structure.