Pharmacological characterization of agonists at delta-containing GABAA receptors: Functional selectivity for extrasynaptic receptors is dependent on the absence of gamma2.
Several groups have characterized the pharmacology of alpha4- or alpha6beta3delta-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 alpha subunit and little on the beta and gamma 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 alpha4beta3, alpha4beta3delta, and alpha6beta3delta receptors expressed in Xenopus oocytes. Little or no difference was seen when the compounds were compared at alphabeta- and alphabetadelta-containing receptors, whereas a significant reduction in both potency and relative efficacy was observed compared with alphabetagamma-containing receptors described in the literature. These data clearly confirm that the presence of the delta subunit in heterotrimeric receptors is a strong determinant of the increased pharmacological activity of compounds with agonist activity. The very similar agonist pharmacology of alphabeta- and alphabetadelta-containing receptors, which is significantly different from that of alphabetagamma-containing receptors, shows that whereas the presence of a gamma subunit impairs the response to an agonist stimulation of the alphabeta receptor complex, the delta subunit does not affect this in any way. Taken together, these data are well in line with the idea that alpha4beta3delta 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.
Stórustovu
Signe I
SI
Department of Electrophysiology, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
Ebert
Bjarke
B
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D007811:Lanthanum / Q000494:pharmacology; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000737:chemistry; D011994:Recombinant Proteins / Q000187:drug effects; D014982:Xenopus laevis; D015032:Zinc / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D007811:Lanthanum; D015032:Zinc; C015542:gaboxadol