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.
From molecular phylogeny towards differentiating pharmacology for NMDA receptor subtypes.
Platt RJ
,
Curtice KJ
,
Twede VD
,
Watkins M
,
Gruszczyński P
,
Bulaj G
,
Horvath MP
,
Olivera BM
.
???displayArticle.abstract???
In order to decode the roles that N-methyl-D-aspartate (NMDA) receptors play in excitatory neurotransmission, synaptic plasticity, and neuropathologies, there is need for ligands that differ in their subtype selectivity. The conantokin family of Conus peptides is the only group of peptidic natural products known to target NMDA receptors. Using a search that was guided by phylogeny, we identified new conantokins from the marine snail Conus bocki that complement the current repertoire of NMDA receptor pharmacology. Channel currents measured in Xenopus oocytes demonstrate conantokins conBk-A, conBk-B, and conBk-C have highest potencies for NR2D containing receptors, in contrast to previously characterized conantokins that preferentially block NR2B containing NMDA receptors. Conantokins are rich in γ-carboxyglutamate, typically 17-34 residues, and adopt helical structure in a calcium-dependent manner. As judged by CD spectroscopy, conBk-C adopts significant helical structure in a calcium ion-dependent manner, while calcium, on its own, appears insufficient to stabilize helical conformations of conBk-A or conBk-B. Molecular dynamics simulations help explain the differences in calcium-stabilized structures. Two-dimensional NMR spectroscopy shows that the 9-residue conBk-B is relatively unstructured but forms a helix in the presence of TFE and calcium ions that is similar to other conantokin structures. These newly discovered conantokins hold promise that further exploration of small peptidic antagonists will lead to a set of pharmacological tools that can be used to characterize the role of NMDA receptors in nervous system function and disease.
Acklin,
5-Aminomethylquinoxaline-2,3-diones, Part III: Arylamide derivatives as highly potent and selective glycine-site NMDA receptor antagonists.
1998, Pubmed
Acklin,
5-Aminomethylquinoxaline-2,3-diones, Part III: Arylamide derivatives as highly potent and selective glycine-site NMDA receptor antagonists.
1998,
Pubmed
Ametamey,
Synthesis, radiolabelling and biological characterization of (D)-7-iodo-N-(1-phosphonoethyl)-5-aminomethylquinoxaline-2,3-dione, a glycine-binding site antagonist of NMDA receptors.
2000,
Pubmed
Auberson,
N-phosphonoalkyl-5-aminomethylquinoxaline-2,3-diones: in vivo active AMPA and NMDA(glycine) antagonists.
1999,
Pubmed
Auberson,
5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition.
2002,
Pubmed
Bashford,
Generalized born models of macromolecular solvation effects.
2000,
Pubmed
Blandl,
Binding of cations to individual gamma-carboxyglutamate residues of conantokin-G and conantokin-T.
1999,
Pubmed
Blandl,
NMDA-receptor antagonist requirements in conantokin-G.
1998,
Pubmed
Blandl,
Sequence requirements for the N-methyl-D-aspartate receptor antagonist activity of conantokin-R.
2001,
Pubmed
Blandl,
Structure-function relationships of the NMDA receptor antagonist peptide, conantokin-R.
2000,
Pubmed
Bulaj,
Integrating the discovery pipeline for novel compounds targeting ion channels.
2008,
Pubmed
Case,
The Amber biomolecular simulation programs.
2005,
Pubmed
Chandler,
Polyamine-like actions of peptides derived from conantokin-G, an N-methyl-D-aspartate (NMDA) antagonist.
1993,
Pubmed
Choi,
Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor.
1999,
Pubmed
,
Xenbase
Costa,
N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives: preferential blockade of extrasynaptic NMDA receptors in the rat hippocampal CA3-CA1 synapse.
2009,
Pubmed
,
Xenbase
Counihan,
Expression of N-methyl-D-aspartate receptor subunit mRNA in the human brain: mesencephalic dopaminergic neurons.
1998,
Pubmed
Cull-Candy,
NMDA receptor subunits: diversity, development and disease.
2001,
Pubmed
Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed
Donevan,
Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors.
2000,
Pubmed
,
Xenbase
Feng,
Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid.
2004,
Pubmed
,
Xenbase
Hammerland,
Conantokin-G selectively inhibits N-methyl-D-aspartate-induced currents in Xenopus oocytes injected with mouse brain mRNA.
1992,
Pubmed
,
Xenbase
Hollmann,
Cloned glutamate receptors.
1994,
Pubmed
Hummel,
Anatomical localization and expression pattern for the NMDA-2D receptor subunit in a rat model of neuropathic pain.
2008,
Pubmed
Jones,
Protein secondary structure prediction based on position-specific scoring matrices.
1999,
Pubmed
Kabsch,
Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features.
1983,
Pubmed
Karlsson,
Glutamate-induced currents reveal three functionally distinct NMDA receptor populations in rat dorsal horn - effects of peripheral nerve lesion and inflammation.
2002,
Pubmed
Khosravani,
Prion protein attenuates excitotoxicity by inhibiting NMDA receptors.
2008,
Pubmed
Kinarsky,
Identification of subunit- and antagonist-specific amino acid residues in the N-Methyl-D-aspartate receptor glutamate-binding pocket.
2005,
Pubmed
,
Xenbase
Klein,
Inhibition of MK801 binding in adult rat brain sections by conantokin-G and conantokin-T.
1999,
Pubmed
Kosinski,
Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: striatum and globus pallidus.
1998,
Pubmed
Layer,
Conantokins: peptide antagonists of NMDA receptors.
2004,
Pubmed
Lin,
Role of modified glutamic acid in the helical structure of conantokin-T.
1997,
Pubmed
Low,
Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors.
2000,
Pubmed
,
Xenbase
Micu,
NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia.
2006,
Pubmed
Minami,
Characterization of the glutamatergic system for induction and maintenance of allodynia.
2001,
Pubmed
Morley,
Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists.
2005,
Pubmed
,
Xenbase
Mosley,
Quinazolin-4-one derivatives: A novel class of noncompetitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists.
2010,
Pubmed
,
Xenbase
Mosley,
Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-D-aspartate receptors.
2009,
Pubmed
,
Xenbase
Olivera,
Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery.
2007,
Pubmed
Olivera,
Conus peptides: biodiversity-based discovery and exogenomics.
2006,
Pubmed
Paoletti,
High-affinity zinc inhibition of NMDA NR1-NR2A receptors.
1997,
Pubmed
,
Xenbase
Rachline,
The micromolar zinc-binding domain on the NMDA receptor subunit NR2B.
2005,
Pubmed
,
Xenbase
Rigby,
Role of gamma-carboxyglutamic acid in the calcium-induced structural transition of conantokin G, a conotoxin from the marine snail Conus geographus.
1997,
Pubmed
Schüler,
Formation of NR1/NR2 and NR1/NR3 heterodimers constitutes the initial step in N-methyl-D-aspartate receptor assembly.
2008,
Pubmed
,
Xenbase
Schwieters,
Internal coordinates for molecular dynamics and minimization in structure determination and refinement.
2001,
Pubmed
Schwieters,
The Xplor-NIH NMR molecular structure determination package.
2003,
Pubmed
Sheng,
Specific determinants of conantokins that dictate their selectivity for the NR2B subunit of N-methyl-D-aspartate receptors.
2010,
Pubmed
Sheng,
Subtype-selective antagonism of N-methyl-D-aspartate receptor ion channels by synthetic conantokin peptides.
2007,
Pubmed
Sheng,
The selectivity of conantokin-G for ion channel inhibition of NR2B subunit-containing NMDA receptors is regulated by amino acid residues in the S2 region of NR2B.
2009,
Pubmed
Simeone,
Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system.
2004,
Pubmed
Skjaerbaek,
Determination of the solution structures of conantokin-G and conantokin-T by CD and NMR spectroscopy.
1997,
Pubmed
Teichert,
Novel conantokins from Conus parius venom are specific antagonists of N-methyl-D-aspartate receptors.
2007,
Pubmed
Tsai,
The effects of alanine-substituted conantokin-G and ifenprodil on the human spermine-activated N-methyl-D-aspartate receptor.
2005,
Pubmed
Twede,
Neuroprotective and cardioprotective conopeptides: an emerging class of drug leads.
2009,
Pubmed
Twede,
Conantokin-Br from Conus brettinghami and selectivity determinants for the NR2D subunit of the NMDA receptor.
2009,
Pubmed
,
Xenbase
Warder,
The roles of individual gamma-carboxyglutamate residues in the solution structure and cation-dependent properties of conantokin-T.
1998,
Pubmed
Warder,
Amino acid determinants for NMDA receptor inhibition by conantokin-T.
2001,
Pubmed
Warder,
The NMR solution structure of the NMDA receptor antagonist, conantokin-T, in the absence of divalent metal ions.
1997,
Pubmed
Wilson,
μ-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve.
2011,
Pubmed
,
Xenbase
Wittekindt,
Point mutations identify the glutamate binding pocket of the N-methyl-D-aspartate receptor as major site of conantokin-G inhibition.
2001,
Pubmed
,
Xenbase
