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.
Mol Pharmacol
2013 Feb 01;832:354-66. doi: 10.1124/mol.112.081794.
Show Gene links
Show Anatomy links
Noncompetitive, voltage-dependent NMDA receptor antagonism by hydrophobic anions.
Linsenbardt AJ, Chisari M, Yu A, Shu HJ, Zorumski CF, Mennerick S.
???displayArticle.abstract???
NMDA receptor (NMDAR) antagonists are dissociative anesthetics, drugs of abuse, and are of therapeutic interest in neurodegeneration and neuropsychiatric disease. Many well-known NMDAR antagonists are positively charged, voltage-dependent channel blockers. We recently showed that the hydrophobic anion dipicrylamine (DPA) negatively regulates GABA(A) receptor function by a mechanism indistinguishable from that of sulfated neurosteroids. Because sulfated neurosteroids also modulate NMDARs, here we examined the effects of DPA on NMDAR function. In rat hippocampal neurons DPA inhibited currents gated by 300 µM NMDA with an IC(50) of 2.3 µM. Neither onset nor offset of antagonism exhibited dependence on channel activation but exhibited a noncompetitive profile. DPA antagonism was independent of NMDAR subunit composition and was similar at extrasynaptic and total receptor populations. Surprisingly, similar to cationic channel blockers but unlike sulfated neurosteroids, DPA antagonism was voltage dependent. Onset and offset of DPA antagonism were nearly 10-fold faster than DPA-induced increases in membrane capacitance, suggesting that membrane interactions do not directly explain antagonism. Furthermore, voltage dependence did not derive from association of DPA with a site on NMDARs directly accessible to the outer membrane leaflet, assessed by DPA translocation experiments. Consistent with the expected lack of channel block, DPA antagonism did not interact with permeant ions. Therefore, we speculate that voltage dependence may arise from interactions of DPA with the inherent voltage dependence of channel gating. Overall, we conclude that DPA noncompetitively inhibits NMDA-induced current by a novel voltage-dependent mechanism and represents a new class of anionic NMDAR antagonists.
Anderson,
Voltage clamp analysis of acetylcholine produced end-plate current fluctuations at frog neuromuscular junction.
1973, Pubmed
Anderson,
Voltage clamp analysis of acetylcholine produced end-plate current fluctuations at frog neuromuscular junction.
1973,
Pubmed Antonov,
Binding sites for permeant ions in the channel of NMDA receptors and their effects on channel block.
1998,
Pubmed Antonov,
Permeant ion regulation of N-methyl-D-aspartate receptor channel block by Mg(2+).
1999,
Pubmed Ascher,
The role of divalent cations in the N-methyl-D-aspartate responses of mouse central neurones in culture.
1988,
Pubmed Benz,
Transport kinetics of hydrophobic ions in lipid bilayer membranes. Charge-pulse relaxation studies.
1976,
Pubmed Boeckman,
Pharmacological properties of acquired excitotoxicity in Chinese hamster ovary cells transfected with N-methyl-D-aspartate receptor subunits.
1996,
Pubmed Bojesen,
Binding of anandamide to bovine serum albumin.
2003,
Pubmed Borovska,
Access of inhibitory neurosteroids to the NMDA receptor.
2012,
Pubmed Boulter,
Molecular cloning and functional expression of glutamate receptor subunit genes.
1990,
Pubmed
,
Xenbase Bradley,
Submillisecond optical reporting of membrane potential in situ using a neuronal tracer dye.
2009,
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 Chang,
Rapid activation of dormant presynaptic terminals by phorbol esters.
2010,
Pubmed Chen,
Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism.
1997,
Pubmed Chisari,
Hydrophobic anions potently and uncompetitively antagonize GABA(A) receptor function in the absence of a conventional binding site.
2011,
Pubmed
,
Xenbase Clark,
The effect of agonist concentration, membrane voltage and calcium on N-methyl-D-aspartate receptor desensitization.
1990,
Pubmed Clarke,
Voltage-dependent gating of NR1/2B NMDA receptors.
2008,
Pubmed Collingridge,
Receptor trafficking and synaptic plasticity.
2004,
Pubmed Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed Fernández,
Induced capacitance in the squid giant axon. Lipophilic ion displacement currents.
1983,
Pubmed Gibbs,
Sulfated steroids as endogenous neuromodulators.
2006,
Pubmed Gilling,
Potency, voltage-dependency, agonist concentration-dependency, blocking kinetics and partial untrapping of the uncompetitive N-methyl-D-aspartate (NMDA) channel blocker memantine at human NMDA (GluN1/GluN2A) receptors.
2009,
Pubmed Hardingham,
Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways.
2002,
Pubmed Harris,
Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices.
2007,
Pubmed Horak,
Subtype-dependence of N-methyl-D-aspartate receptor modulation by pregnenolone sulfate.
2006,
Pubmed Huettner,
Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels.
1988,
Pubmed Jahr,
A quantitative description of NMDA receptor-channel kinetic behavior.
1990,
Pubmed Jin,
Kinetic analysis of voltage-dependent potentiation and block of the glycine alpha 3 receptor by a neuroactive steroid analogue.
2009,
Pubmed
,
Xenbase Kashiwagi,
Channel blockers acting at N-methyl-D-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore.
2002,
Pubmed
,
Xenbase Ketterer,
Transport mechanism of hydrophobic ions through lipid bilayer membranes.
1971,
Pubmed Lu,
Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons.
2001,
Pubmed MacDonald,
Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine.
1987,
Pubmed MacDonald,
Mechanisms of blockade of excitatory amino acid receptor channels.
1990,
Pubmed Malayev,
Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids.
2002,
Pubmed
,
Xenbase Mealing,
Differences in degree of trapping of low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists with similar kinetics of block.
1999,
Pubmed Mennerick,
Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures.
1998,
Pubmed Mennerick,
Passive and synaptic properties of hippocampal neurons grown in microcultures and in mass cultures.
1995,
Pubmed Monyer,
Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.
1994,
Pubmed Nakazawa,
NMDA receptors, place cells and hippocampal spatial memory.
2004,
Pubmed Nowak,
Slow voltage-dependent changes in channel open-state probability underlie hysteresis of NMDA responses in Mg(2+)-free solutions.
1992,
Pubmed Nowak,
Magnesium gates glutamate-activated channels in mouse central neurones.
,
Pubmed Orser,
Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors.
1997,
Pubmed Paoletti,
High-affinity zinc inhibition of NMDA NR1-NR2A receptors.
1997,
Pubmed
,
Xenbase Park-Chung,
Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by sulfated steroids.
1997,
Pubmed
,
Xenbase Park-Chung,
3 alpha-Hydroxy-5 beta-pregnan-20-one sulfate: a negative modulator of the NMDA-induced current in cultured neurons.
1994,
Pubmed Petrovic,
20-oxo-5beta-pregnan-3alpha-yl sulfate is a use-dependent NMDA receptor inhibitor.
2005,
Pubmed Richieri,
Interactions of long-chain fatty acids and albumin: determination of free fatty acid levels using the fluorescent probe ADIFAB.
1993,
Pubmed Rosenmund,
Synaptic NMDA receptor channels have a low open probability.
1995,
Pubmed Sobolevsky,
Probing of NMDA channels with fast blockers.
1999,
Pubmed Tong,
Synaptic desensitization of NMDA receptors by calcineurin.
1995,
Pubmed Tovar,
The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro.
1999,
Pubmed Weaver,
Geometry and charge determine pharmacological effects of steroids on N-methyl-D-aspartate receptor-induced Ca(2+) accumulation and cell death.
2000,
Pubmed Weiss,
Membrane potential modulates the activation of GABA-gated channels.
1988,
Pubmed Woodhull,
Ionic blockage of sodium channels in nerve.
1973,
Pubmed Wroge,
Synaptic NMDA receptors mediate hypoxic excitotoxic death.
2012,
Pubmed Yang,
Ionic flow enhances low-affinity binding: a revised mechanistic view into Mg2+ block of NMDA receptors.
2010,
Pubmed
