title: SB-205384 is a positive allosteric modulator of recombinant GABAA receptors containing rat α3, α5, or α6 subunit subtypes coexpressed with β3 and γ2 subunits.
abstract: Many drugs used to treat anxiety are positive modulators of GABAA receptors, which mediate fast inhibitory neurotransmission. The GABAA receptors can be assembled from a combination of at least 16 different subunits. The receptor's subunit composition determines its pharmacologic and functional properties, and subunit expression varies throughout the brain. A primary goal for new treatments targeting GABAA receptors is the production of subunit-selective modulators acting upon a discrete population of receptors. The anxiolytic 4-amino-7-hydroxy-2-methyl-5,6,7,8,-tetrahydrobenzo[b]thieno[2,3-b]pyridine-3-carboxylic acid, but-2-ynyl ester (SB-205384) is widely considered to be selective for α3-containing GABAA receptors. However, it has been tested only on α1-, α2-, and α3-containing receptors. We examined the activity of SB-205384 at recombinant receptors containing the six different α subunits and found that receptors containing the α3, α5, and α6 subunits were potentiated by SB-205384, with the α6 subunit conferring the greatest responsiveness. Properties associated with chimeric α1/α6 subunits suggested that multiple structural domains influence sensitivity to SB-205384. Point mutations of residues within the extracellular N-terminal domain identified a leucine residue located in loop E of the agonist binding site as an important determinant of high sensitivity to modulation. In the α6 subunit the identity of this residue is species-dependent, with the leucine found in rat subunits but not in human. Our results indicate that SB-205384 is not an α3-selective modulator, and instead acts at several GABAA receptor isoforms. These findings have implications for the side-effect profile of this anxiolytic as well as for its use in neuronal and animal studies as a marker for contribution from α3-containing receptors.
authors.affiliation: Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine Columbia, South Carolina (J.W.W., J.L.F.); and Honors College, University of South Carolina-Columbia, Columbia, South Carolina (L.S.H.).
authors.forename: Laura S
authors.initials: LS
authors.lastname: Heidelberg
authors.forename: James W
authors.initials: JW
authors.lastname: Warren
authors.forename: Janet L
authors.initials: JL
authors.lastname: Fisher
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; C546257:GABRA3 protein, human; C546171:GABRA6 protein, human; C546279:GABRG2 protein, human; C511535:Gabra5 protein, rat; C546276:Gabrb3 protein, rat; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D013876:Thiophenes; C108120:SB 205384
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