Recent advances in molecular biology and complementary information derived from neuropharmacology, biochemistry and behavior have dramatically increased our understanding of various aspects of GABAA receptors. These studies have revealed that the GABAA receptor is derived from various subunits such as alpha1-alpha6, beta1-beta3, gamma1-gamma3, delta, epsilon, pi, and rho1-3. Furthermore, two additional subunits (beta4, gamma4) of GABAA receptors in chick brain, and five isoforms of the rho-subunit in the retina of white perch (Roccus americana) have been identified. Various techniques such as mutation, gene knockout and inhibition of GABAA receptor subunits by antisense oligodeoxynucleotides have been used to establish the physiological/pharmacological significance of the GABAA receptor subunits and their native receptor assemblies in vivo. Radioligand binding to the immunoprecipitated receptors, co-localization studies using immunoaffinity chromatography and immunocytochemistry techniques have been utilized to establish the composition and pharmacology of native GABAA receptor assemblies. Partial agonists of GABAA receptors are being developed as anxiolytics which have fewer and less severe side effects as compared to conventional benzodiazepines because of their lower efficacy and better selectivity for the GABAA receptor subtypes. The subunit requirement of various drugs such as anxiolytics, anticonvulsants, general anesthetics, barbiturates, ethanol and neurosteroids, which are known to elicit at least some of their pharmacological effects via the GABAA receptors, have been investigated during the last few years so as to understand their exact mechanism of action. Furthermore, the molecular determinants of clinically important drug-targets have been investigated. These aspects of GABAA receptors have been discussed in detail in this review article.
Copyright 1999 Elsevier Science B.V.