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Structurally diverse amphiphiles exhibit biphasic modulation of GABAA receptors: similarities and differences with neurosteroid actions.

Abstract：

BACKGROUND AND PURPOSE:Some neurosteroids, notably 3alpha-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-beta-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 microM) promoted potentiation and a high concentration (20 microM) 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 (alpha1V256S) and positive (alpha1Q241L or alpha1N407A/Y410F) steroid modulation. Negative regulation by amphiphiles was nearly abolished in alpha1V256S-mutated receptors, but potentiation was unaffected. In alpha1Q241L- or alpha1N407A/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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Chisari M,Shu HJ,Taylor A,Steinbach JH,Zorumski CF,Mennerick S

doi

10.1111/j.1476-5381.2010.00679.x

subject

Has Abstract

pub_date

2010-05-01 00:00:00

pages

130-41

issue

eissn

0007-1188

issn

1476-5381

pii

BPH679

journal_volume

160

pub_type

杂志文章

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Structurally diverse amphiphiles exhibit biphasic modulation of GABAA receptors: similarities and differences with neurosteroid actions.