Triton X-100 inhibits agonist-induced currents and suppresses benzodiazepine modulation of GABA(A) receptors in Xenopus oocytes.
Changes in lipid bilayer elastic properties have been proposed to underlie the modulation of voltage-gated Na(+) and L-type Ca(2+) channels and GABA(A) receptors by amphiphiles. The amphiphile Triton X-100 increases the elasticity of lipid bilayers at micromolar concentrations, assessed from its effects on gramicidin channel A appearance rate and lifetime in artificial lipid bilayers. In the present study, the pharmacological action of Triton-X 100 on GABA(A) receptors expressed in Xenopus laevis oocytes was examined. Triton-X 100 inhibited GABA(A) alpha(1)beta(3)gamma(2S) receptor currents in a noncompetitive, time- and voltage-dependent manner and increased the apparent rate and extent of desensitization at 10 muM, which is 30 fold below the critical micelle concentration. In addition, Triton X-100 induced picrotoxin-sensitive GABA(A) receptor currents and suppressed allosteric modulation by flunitrazepam at alpha(1)beta(3)gamma(2S) receptors. All effects were independent of the presence of a gamma(2S) subunit in the GABA(A) receptor complex. The present study suggests that Triton X-100 may stabilize open and desensitized states of the GABA(A) receptor through changes in lipid bilayer elasticity.
Søgaard
Rikke
R
Institute of Cellular and Molecular Medicine, Panum 12.6, University of Copenhagen, Blegdamsvej 3C, DK-2200, Copenhagen N, Denmark. rikkes@sund.ku.dk
Ebert
Bjarke
B
Klaerke
Dan
D
Werge
Thomas
T
D000818:Animals; D055592:Biophysical Phenomena; D055724:Electrophysiological Phenomena; D005260:Female; D005445:Flunitrazepam / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D066298:In Vitro Techniques; D008051:Lipid Bilayers; D017830:Octoxynol / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D013501:Surface-Active Agents / Q000494:pharmacology; D014982:Xenopus laevis
D005445:Flunitrazepam; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D008051:Lipid Bilayers; D017830:Octoxynol; D010852:Picrotoxin; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D013501:Surface-Active Agents