title: GABA(A) receptor function is regulated by lipid bilayer elasticity.
abstract: Docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) promote GABA(A) receptor [(3)H]-muscimol binding, and DHA increases the rate of GABA(A) receptor desensitization. Triton X-100, a structurally unrelated amphiphile, similarly promotes [(3)H]-muscimol binding. The mechanism(s) underlying these effects are poorly understood. DHA and Triton X-100, at concentrations that affect GABA(A) receptor function, increase the elasticity of lipid bilayers measured as decreased bilayer stiffness using gramicidin channels as molecular force transducers. We have previously shown that membrane protein function can be regulated by amphiphile-induced changes in bilayer elasticity and hypothesized that GABA(A) receptors could be similarly regulated. We therefore studied the effects of four structurally unrelated amphiphiles that decrease bilayer stiffness (Triton X-100, octyl-beta-glucoside, capsaicin, and DHA) on GABA(A) receptor function in mammalian cells. All the compounds promoted GABA(A) receptor [(3)H]-muscimol binding by increasing the binding capacity of high-affinity binding without affecting the associated equilibrium binding constant. A semiquantitative analysis found a similar quantitative relation between the effects on bilayer stiffness and [(3)H]-muscimol binding. Membrane cholesterol depletion, which also decreases bilayer stiffness, similarly promoted [(3)H]-muscimol binding. In whole-cell voltage-clamp experiments, Triton X-100, octyl-beta-glucoside, capsaicin, and DHA all reduced the peak amplitude of the GABA-induced currents and increased the rate of receptor desensitization. The effects of the amphiphiles did not correlate with the expected changes in monolayer spontaneous curvature. We conclude that GABA(A) receptor function is regulated by lipid bilayer elasticity. PUFAs may generally regulate membrane protein function by affecting the elasticity of the host lipid bilayer.
authors.affiliation: Research Institute of Biological Psychiatry, Sct. Hans Hospital, Boserupvej 2, DK-4000 Roskilde, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Søgaard
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Werge
authors.forename: Camilla
authors.initials: C
authors.lastname: Bertelsen
authors.forename: Camilla
authors.initials: C
authors.lastname: Lundbye
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Madsen
authors.forename: Claus H
authors.initials: CH
authors.lastname: Nielsen
authors.forename: Jens A
authors.initials: JA
authors.lastname: Lundbaek
mesh_terms: D000818:Animals; D016466:CHO Cells; D002211:Capsaicin / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology; D005960:Glucosides / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008560:Membrane Fluidity / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D009118:Muscimol / Q000378:metabolism; D017830:Octoxynol / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D014316:Tritium
chemical_list: D005960:Glucosides; D007473:Ion Channels; D008051:Lipid Bilayers; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D014316:Tritium; D004281:Docosahexaenoic Acids; D009118:Muscimol; C018619:octyl-beta-D-glucoside; D017830:Octoxynol; D002211:Capsaicin