Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Hydrophobic anions potently and uncompetitively antagonize GABA(A) receptor function in the absence of a conventional binding site.
Chisari M
,
Wu K
,
Zorumski CF
,
Mennerick S
.
???displayArticle.abstract???
A 'lock-and-key' binding site typically accounts for the effect of receptor antagonists. However, sulphated neurosteroids are potent non-competitive antagonists of GABA(A) receptors without a clear structure-activity relationship. To gain new insights, we tested two structurally unrelated hydrophobic anions with superficially similar properties to sulphated neurosteroids.We used voltage-clamp techniques in Xenopus oocytes and hippocampal neurons to characterize dipicrylamine (DPA) and tetraphenylborate (TPB), compounds previously used to probe membrane structure and voltage-gated ion channel function.Both DPA and TPB potently antagonized GABA(A) receptors. DPA exhibited an IC₅₀ near 60 nM at half-maximal GABA concentration and antagonism with features indistinguishable from pregnenolone sulphate antagonism, including sensitivity to a point mutation in transmembrane domain 2 of the α1 subunit. Bovine serum albumin, which scavenges free membrane-associated DPA, accelerated both capacitance offset and antagonism washout. Membrane interactions and antagonism were explored using the voltage-dependent movement of DPA between membrane leaflets. Washout of DPA antagonism was strongly voltage-dependent, paralleling DPA membrane loss, although steady-state antagonism lacked voltage dependence. At antagonist concentrations, DPA failed to affect inhibitory post-synaptic current (IPSC) amplitude or decay, but DPA accelerated pharmacologically prolonged IPSCs.Neurosteroid-like GABA(A) receptor antagonism appears to lacks a conventional binding site. These features highlight key roles of membrane interactions in antagonism. Because its membrane mobility can be controlled, DPA may be a useful probe of GABA(A) receptors, but its effects on excitability via GABA(A) receptors raise caveats for its use in monitoring neuronal activity.
Akk,
Neurosteroid access to the GABAA receptor.
2005, Pubmed
Akk,
Neurosteroid access to the GABAA receptor.
2005,
Pubmed
Akk,
Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit.
2001,
Pubmed
Andersen,
Potential energy barriers to ion transport within lipid bilayers. Studies with tetraphenylborate.
1975,
Pubmed
Bekkers,
Excitatory and inhibitory autaptic currents in isolated hippocampal neurons maintained in cell culture.
1991,
Pubmed
Benz,
Transport kinetics of dipicrylamine through lipid bilayer membranes. Effects of membrane structure.
1977,
Pubmed
Benz,
Transport kinetics of hydrophobic ions in lipid bilayer membranes. Charge-pulse relaxation studies.
1976,
Pubmed
Bradley,
Submillisecond optical reporting of membrane potential in situ using a neuronal tracer dye.
2009,
Pubmed
Bruner,
The interaction of hydrophobic ions with lipid bilayer membranes.
1975,
Pubmed
Capogna,
GABA A,slow: causes and consequences.
2011,
Pubmed
Chanda,
Gating charge displacement in voltage-gated ion channels involves limited transmembrane movement.
2005,
Pubmed
Chanda,
A hybrid approach to measuring electrical activity in genetically specified neurons.
2005,
Pubmed
Chen,
Structural model for gamma-aminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site.
2006,
Pubmed
Chisari,
The influence of neuroactive steroid lipophilicity on GABAA receptor modulation: evidence for a low-affinity interaction.
2009,
Pubmed
,
Xenbase
Chisari,
Structurally diverse amphiphiles exhibit biphasic modulation of GABAA receptors: similarities and differences with neurosteroid actions.
2010,
Pubmed
,
Xenbase
Chisari,
The sticky issue of neurosteroids and GABA(A) receptors.
2010,
Pubmed
Ebert,
Molecular pharmacology of gamma-aminobutyric acid type A receptor agonists and partial agonists in oocytes injected with different alpha, beta, and gamma receptor subunit combinations.
1994,
Pubmed
,
Xenbase
Eisenman,
Activation-dependent properties of pregnenolone sulfate inhibition of GABAA receptor-mediated current.
2003,
Pubmed
,
Xenbase
Fernández,
Induced capacitance in the squid giant axon. Lipophilic ion displacement currents.
1983,
Pubmed
Fritschy,
GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits.
1995,
Pubmed
Hille,
Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction.
1977,
Pubmed
Johnson,
Mechanism of action of memantine.
2006,
Pubmed
Ketterer,
Transport mechanism of hydrophobic ions through lipid bilayer membranes.
1971,
Pubmed
Klaassen,
Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy.
2006,
Pubmed
Lee,
A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom.
2004,
Pubmed
Li,
Enantiomers of neuroactive steroids support a specific interaction with the GABA-C receptor as the mechanism of steroid action.
2006,
Pubmed
,
Xenbase
Lundbaek,
Lipid bilayer-mediated regulation of ion channel function by amphiphilic drugs.
2008,
Pubmed
Maconochie,
How quickly can GABAA receptors open?
1994,
Pubmed
Mennerick,
Effects on membrane capacitance of steroids with antagonist properties at GABAA receptors.
2008,
Pubmed
,
Xenbase
Mennerick,
Passive and synaptic properties of hippocampal neurons grown in microcultures and in mass cultures.
1995,
Pubmed
Mody,
Diversity of inhibitory neurotransmission through GABA(A) receptors.
2004,
Pubmed
NULL,
Guide to Receptors and Channels (GRAC), 4th Edition.
2009,
Pubmed
Nilsson,
Neurosteroid analogues. 6. The synthesis and GABAA receptor pharmacology of enantiomers of dehydroepiandrosterone sulfate, pregnenolone sulfate, and (3alpha,5beta)-3-hydroxypregnan-20-one sulfate.
1998,
Pubmed
Pennefather,
Modification of dose-response curves by effector blockade and uncompetitive antagonism.
1982,
Pubmed
Pytel,
Membrane voltage modulates the GABA(A) receptor gating in cultured rat hippocampal neurons.
2006,
Pubmed
Rosenmund,
Nonuniform probability of glutamate release at a hippocampal synapse.
1993,
Pubmed
Shen,
Pregnenolone sulfate modulates inhibitory synaptic transmission by enhancing GABA(A) receptor desensitization.
2000,
Pubmed
Shu,
Slow actions of neuroactive steroids at GABAA receptors.
2004,
Pubmed
,
Xenbase
Shu,
Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions.
2007,
Pubmed
,
Xenbase
Swanwick,
Development of gamma-aminobutyric acidergic synapses in cultured hippocampal neurons.
2006,
Pubmed
Søgaard,
GABA(A) receptor function is regulated by lipid bilayer elasticity.
2006,
Pubmed
Twede,
The neurosteroids dehydroepiandrosterone sulfate and pregnenolone sulfate inhibit the UNC-49 GABA receptor through a common set of residues.
2007,
Pubmed
,
Xenbase
Wang,
3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists.
2002,
Pubmed
,
Xenbase
Weiss,
Membrane potential modulates the activation of GABA-gated channels.
1988,
Pubmed
Yoon,
Multiple mechanisms of picrotoxin block of GABA-induced currents in rat hippocampal neurons.
1993,
Pubmed
