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NEUROPHARMACOLOGY

Pharmacological Characterization of Agonists at -Containing GABA_A Receptors: Functional Selectivity for Extrasynaptic Receptors Is Dependent on the Absence of ₂

Department of Electrophysiology, H. Lundbeck A/S, Valby, Denmark

Several groups have characterized the pharmacology of ₄- or ₆₃-containing GABA_A receptors expressed in different cell systems. We have previously demonstrated that the pharmacological profiles of a series of GABA_A receptor agonists are highly dependent on the subunit and little on the and subunits, so to further understand the contribution of the different subunits in the GABA_A receptor complex, we characterized a series of full agonists, partial agonists, and antagonists at ₄₃, ₄₃, and ₆₃ receptors expressed in Xenopus oocytes. Little or no difference was seen when the compounds were compared at - and -containing receptors, whereas a significant reduction in both potency and relative efficacy was observed compared with -containing receptors described in the literature. These data clearly confirm that the presence of the subunit in heterotrimeric receptors is a strong determinant of the increased pharmacological activity of compounds with agonist activity. The very similar agonist pharmacology of - and -containing receptors, which is significantly different from that of -containing receptors, shows that whereas the presence of a subunit impairs the response to an agonist stimulation of the receptor complex, the subunit does not affect this in any way. Taken together, these data are well in line with the idea that ₄₃ 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 GABA_A agonists.

Address correspondence to: Dr. Bjarke Ebert, Department of Electrophysiology, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark. E-mail: bjeb{at}lundbeck.com

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