Structurally diverse amphiphiles exhibit biphasic modulation of GABA _A receptors: Similarities and differences with neurosteroid actions

Background and purpose: Some neurosteroids, notably 3α- hydroxysteroids, positively modulate GABA _A receptors, but sulphated steroids negatively modulate these receptors. Recently, other lipophilic amphiphiles have been suggested to positively modulate GABA receptors. We examined whether there was similarity among the actions of these agents and the mechanisms of neurosteroids. Significant similarity would affect theories about the specificity of steroid actions. Experimental approach: Xenopus laevis oocytes were challenged with Triton X-100, octyl-β-glucoside, capsaicin, docosahexaenoic acid and sodium dodecyl sulphate (SDS), along with different GABA concentrations. Key results: These compounds have both positive and negative effects on GABA currents, which can be accentuated according to the degree of receptor activation. A low GABA concentration (1 μM) promoted potentiation and a high concentration (20 μM) promoted inhibition of current, except for SDS that inhibited function even at low GABA concentrations. Amphiphile inhibition was characterized by enhanced apparent desensitization and by weak voltage dependence, similar to pregnenolone sulphate antagonism. We then tested amphiphile effects on mutated receptor subunits that are insensitive to negative (α1V256S) and positive (α1Q241L or α1N407A/Y410F) steroid modulation. Negative regulation by amphiphiles was nearly abolished in α1V256S-mutated receptors, but potentiation was unaffected. In α1Q241L- or α1N407A/Y410F-mutated receptors, potentiation by amphiphiles remained intact. Conclusions and implications: Structurally diverse amphiphiles have antagonist actions at GABA _A receptors very similar to those of sulphated neurosteroids, while the potentiating mechanisms of these amphiphiles are distinct from those of neurosteroid-positive modulators. Thus, such antagonism at GABA _A receptors does not have a clear pharmacophore requirement.