Unexpected Properties of [delta]-Containing GABA^sub A^ Receptors in Response to Ligands Interacting with the [alpha]+ [beta]- Site

Issue Title: Special Issue Dedicated to Richard W. Olsen GABA^sub A^ receptors are the major inhibitory neurotransmitter receptors in the central nervous system and are the targets of many clinically important drugs, which modulate GABA induced chloride flux by interacting with separate and distinct allosteric binding sites. Recently, we described an allosteric modulation occurring upon binding of pyrazoloquinolinones to a novel binding site at the extracellular [alpha]+ [beta]- interface. Here, we investigated the effect of 4-(8-methoxy-3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzonitrile (the pyrazoloquinolinone LAU 177) at several [alpha][beta], [alpha][beta]γ and [alpha][beta]δ receptor subtypes. LAU 177 enhanced GABA-induced currents at all receptors investigated, and the extent of modulation depended on the type of [alpha] and [beta] subunits present within the receptors. Whereas the presence of a γ2 subunit within [alpha][beta]γ2 receptors did not dramatically change LAU 177 induced modulation of GABA currents compared to [alpha][beta] receptors, we observed an unexpected threefold increase in modulatory efficacy of this compound at [alpha]1[beta]2,3δ receptors. Steric hindrance experiments as well as inhibition by the functional [alpha]+ [beta]- site antagonist LAU 157 indicated that the effects of LAU 177 at all receptors investigated were mediated via the [alpha]+ [beta]- interface. The stronger enhancement of GABA-induced currents by LAU 177 at [alpha]1[beta]3δ receptors was not observed at [alpha]4,6[beta]3δ receptors. Other experiments indicated that this enhancement of modulatory efficacy at [alpha]1[beta]3δ receptors was not observed with another [alpha]+ [beta]- modulator, and that the efficacy of modulation by [alpha]+ [beta]- ligands is influenced by all subunits present in the receptor complex and by structural details of the respective ligand.[PUBLICATION ABSTRACT]