RT Journal Article
SR Electronic
T1 SB-205384 is a positive allosteric modulator of recombinant GABAA receptors containing rat α3, α5 or α6 subunit subtypes co-expressed with β3 and γ2 subunits
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.113.207324
DO 10.1124/jpet.113.207324
A1 Laura S Heidelberg
A1 James W Warren
A1 Janet L. Fisher
YR 2013
UL http://jpet.aspetjournals.org/content/early/2013/07/31/jpet.113.207324.abstract
AB 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 pharmacological 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 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.