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


METHODS
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.


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
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.
Chisari
M
M
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
Shu
H-J
HJ
Taylor
A
A
Steinbach
J H
JH
Zorumski
C F
CF
Mennerick
Steven
S
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D018757:GABA Modulators / Q000737:chemistry / Q000494:pharmacology*; D005960:Glucosides / Q000494:pharmacology; D009154:Mutation; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000494:pharmacology*; D017830:Octoxynol / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
D018757:GABA Modulators; D005960:Glucosides; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D013501:Surface-Active Agents; D004281:Docosahexaenoic Acids; C018619:octyl-beta-D-glucoside; D012967:Sodium Dodecyl Sulfate; D017830:Octoxynol; D002211:Capsaicin
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