Pharmacological Characterization of Agonists at δ-Containing GABAA Receptors: Functional Selectivity for Extrasynaptic Receptors Is Dependent on the Absence of γ2

Several groups have characterized the pharmacology of α4- or α6β3δ-containing GABAA receptors expressed in different cell systems. We have previously demonstrated that the pharmacological profiles of a series of GABAA receptor agonists are highly dependent on the α subunit and little on the β and γ subunits, so to further understand the contribution of the different subunits in the GABAA receptor complex, we characterized a series of full agonists, partial agonists, and antagonists at α4β3, α4β3δ, and α6β3δ receptors expressed in Xenopus oocytes. Little or no difference was seen when the compounds were compared at αβ- and αβδ-containing receptors, whereas a significant reduction in both potency and relative efficacy was observed compared with αβγ-containing receptors described in the literature. These data clearly confirm that the presence of the δ subunit in heterotrimeric receptors is a strong determinant of the increased pharmacological activity of compounds with agonist activity. The very similar agonist pharmacology of αβ- and αβδ-containing receptors, which is significantly different from that of αβγ-containing receptors, shows that whereas the presence of a γ subunit impairs the response to an agonist stimulation of the αβ receptor complex, the δ subunit does not affect this in any way. Taken together, these data are well in line with the idea that α4β3δ may contribute to the pharmacological action of exogenously applied agonists and may explain why systemically active compounds such as gaboxadol and muscimol in vivo appear to act as selective extrasynaptic GABAA agonists.