MOLECULAR PHARMACOLOGY OF GAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR AGONISTS AND PARTIAL AGONISTS IN OOCYTES INJECTED WITH DIFFERENT ALPHA-RECEPTOR, BETA-RECEPTOR, AND GAMMA-RECEPTOR SUBUNIT COMBINATIONS

Using systematic combination of alpha 1, alpha 3, and alpha 5 with bet a 1, beta 2, and beta 3, together with gamma 1, gamma 2, and gamma 3, we have investigated the contributions of the various alpha, beta and gamma subunits to the pharmacology of gamma-aminobutyric acid (GABA)(A ) agonists. We have characterized GABA, (RS)-dihydromuscimol, piperidi ne-4-sulfonic acid, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol with recombinant human GABA(A) receptors expressed in Xenopus oocytes . Our observations indicate that the alpha subunit is the major determ inant of efficay for partial GABA(A) agonists. When alpha(1) and alpha 3 or alpha 1 and alpha 5 are coexpressed, the alpha 1 subunit determi nes the maximum efficacy, whereas the affinity is determined by the en tire combination of subunits. Thus, the results of the present study d emonstrate that the pharmacology of GABA(A) agonists is dependent on t he subunit composition of the GABA(A) receptor complex. Functional GAB A(A) receptors containing two different alpha subunits show pharmacolo gical profiles distinctly different from those of receptors containing a single alpha subtype, indicating that two different alpha subunits can be coexpressed in one functional GABA(A) receptor complex.