DIFFERENCES IN AGONIST ANTAGONIST BINDING-AFFINITY AND RECEPTOR TRANSDUCTION USING RECOMBINANT HUMAN GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTORS/

Using human gamma-aminobutyric acid type A (GABA(A)) receptor subunit combinations, expressed in cell lines and Xenopus laevis oocytes, the pharmacology of a number of ligands interacting directly with the GABA recognition site has been studied in [H-3]muscimol binding and electr ophysioloyically. The binding affinity of GABA(A) agonist and antagoni st ligands showed small but statistically significant dependence on th e subunit composition of receptors that include gamma 2 and different alpha and beta subunits. The potency of antagonist ligands was largely independent of receptor subunit composition, whereas the composition of receptors expressed in oocytes strongly influenced the EC50 value o f agonists. An apparent reciprocal correlation between subunits favori ng agonist binding and antagonist binding, respectively, was observed. Whereas antagonists showed comparable potencies in binding and functi onal studies, the potency of agonists in binding studies was generally two to three orders of magnitude higher than the agonist potencies me asured electrophysiologically. 5-(4-Piperidyl)isothiazol-3-ol, which b ehaves as a low efficacy partial agonist at GABA(A) receptors in cultu red cortical neurons, showed no efficacy in oocytes, but produced pure antagonist effects with a binding/functional affinity ratio between t hose observed for the agonists and antagonists. It is concluded that t he GABA(A) receptor mechanisms transducing binding into physiological response, but not the binding per se, is dependent on the receptor sub unit composition.