Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors.

Conantokin G (Con G) is a 17-amino-acid peptide antagonist of N-methyl-D-aspartate (NMDA) receptors isolated from the venom of the marine cone snail, Conus geographus. The mechanism of action of Con G has not been well defined; both competitive and noncompetitive interactions with the NMDA-binding site have been proposed. In this study the mechanism of action and subunit selectivity of Con G was examined in whole-cell voltage-clamp recordings from cultured neurons and in two electrode voltage-clamp recordings from Xenopus oocytes expressing recombinant NMDA receptors. Con G was a potent and selective antagonist of NMDA-evoked currents in murine cortical neurons (IC(50) = 480 nM). The slow onset of Con G block could be prevented by coapplication with high concentrations of NMDA or of the competitive antagonist (RS)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid. Furthermore, in oocytes expressing NR1a/NR2B receptors, Con G produced a rightward shift in the concentration-response curve for NMDA, providing support for a competitive interaction with the NMDA-binding site. Con G produced an apparent noncompetitive shift in the concentration-response curve for spermine potentiation of NMDA responses, but this was due to spermine-induced enhancement of Con G block. Spermine produced a similar enhancement of DL-2-amino-S-phosphopentanoic acid block. Finally, Con G selectively blocked NMDA receptors containing the NR2B subunit. These results demonstrate that Con G is a subunit-specific competitive antagonist of NMDA receptors. The unique subunit selectivity profile of Con G may explain its favorable in vivo profile compared with nonselective NMDA antagonists.

• Publication year

  2000

• Venue

  Molecular Pharmacology

• Publication date

  2000-09-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1124/MOL.58.3.614PMID 10953056
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• In vitro and in vivo characterization of conantokin-R, a selective NMDA receptor antagonist isolated from the venom of the fish-hunting snail Conus radiatus.

  2000cited by this paper
• Conus peptides as probes for ion channels.

  1999cited by this paper
• Gabapentin in the Management of Convulsive Disorders

  1999cited by this paper
• The glutamate receptor ion channels.

  1999cited by this paper
• Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons

  1998cited by this paper
• Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition

  1998cited by this paper
• Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro.

  1997cited by this paper
• The majority of N-methyl-D-aspartate receptor complexes in adult rat cerebral cortex contain at least three different subunits (NR1/NR2A/NR2B).

  1997cited by this paper
• E.E. Just Lecture, 1996. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology.

  1997cited by this paper
• Pharmacological heterogeneity of NMDA receptors: characterization of NR1a/NR2D heteromers expressed in Xenopus oocytes.

  1997cited by this paper
• Molecular Dissection of Native Mammalian Forebrain NMDA Receptors Containing the NR1 C2 Exon: Direct Demonstration of NMDA Receptors Comprising NR1, NR2A, and NR2B Subunits Within the Same Complex

  1997cited by this paper
• Influence of extracellular pH on inhibition by ifenprodil at N-methyl-D-aspartate receptors in Xenopus oocytes.

  1997cited by this paper
• Relationship between N-Methyl-D-aspartate Receptor NR1 Splice Variants and NR2 Subunits*

  1996cited by this paper
• A novel mechanism of activity‐dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones.

  1996cited by this paper
• Synaptic NMDA receptors in developing mouse hippocampal neurones: functional properties and sensitivity to ifenprodil.

  1996cited by this paper
• Multiple actions of arylalkylamine arthropod toxins on the N-methyl-D-aspartate receptor.

  1996cited by this paper
• Interactions between Ifenprodil and the NR2B Subunit of the N-Methyl-D-aspartate Receptor (*)

  1996cited by this paper
• Synthetic Analogues of Conantokin‐G: NMDA Antagonists Acting Through a Novel Polyamine‐Coupled Site

  1996cited by this paper
• Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines.

  1995influential reference
• Release of spermidine from the rat cortex following permanent middle cerebral artery occlusion

  1995cited by this paper
• N-methyl-D-aspartic acid receptor structure and function.

  1994cited by this paper
• Changing subunit composition of heteromeric NMDA receptors during development of rat cortex

  1994cited by this paper
• Molecular characterization of N-methyl-D-aspartate receptors expressed in mammalian cells yields evidence for the coexistence of three subunit types within a discrete receptor molecule.

  1994cited by this paper
• The molecular basis of NMDA receptor subtypes: native receptor diversity is predicted by subunit composition

  1994cited by this paper
• [3H] CGP 39653 Binding to the Agonist Site of the N‐Methyl‐ D‐Aspartate Receptor Is Modulated by Mg2+ and Polyamines Independently of the Arcaine‐Sensitive Polyamine Site

  1994cited by this paper
• Mechanisms influencing stimulatory effects of spermine at recombinant N-methyl-D-aspartate receptors.

  1994influential reference
• N-Methyl-D-aspartate receptors are clustered and immobilized on dendrites of living cortical neurons.

  1993cited by this paper
• Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.

  1993cited by this paper
• Conantokin-G antagonism of the NMDA receptor subtype expressed in cultured cerebellar granule cells.

  1993influential reference
• Splice variants of the N-methyl-D-aspartate receptor NR1 identify domains involved in regulation by polyamines and protein kinase C.

  1993cited by this paper
• Increases in brain polyamine concentrations in chemical kindling and single convulsion induced by pentylenetetrazol in rats.

  1993cited by this paper
• Zinc potentiates agonist-lnduced currents at certain splice variants of the NMDA receptor

  1993cited by this paper
• Conantokin-G selectively inhibits N-methyl-D-aspartate-induced currents in Xenopus oocytes injected with mouse brain mRNA.

  1992cited by this paper
• Selective Release of Spermine and Spermidine from the Rat Striatum by N‐Methyl‐d‐Aspartate Receptor Activation In Vivo

  1992cited by this paper
• Noncompetitive Inhibition of N‐Methyl‐D‐Aspartate by Conantokin‐G: Evidence for an Allosteric Interaction at Polyamine Sites

  1992influential reference
• Potent indole- and quinoline-containing N-methyl-D-aspartate antagonists acting at the strychnine-insensitive glycine binding site.

  1992cited by this paper
• Polyamine uptake, binding and release in rat brain.

  1991cited by this paper
• Conantokin-G: a novel peptide antagonist to the N-methyl-D-aspartic acid (NMDA) receptor.

  1990cited by this paper
• THE SPONTANEOUS AND EVOKED RELEASE OF SPERMINE FROM RAT BRAIN in vitro

  1981cited by this paper

• Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes

  2025cites this paper
• A genetically encoded secreted toxin potentiates synaptic NMDA receptors in hippocampal neurons and confers neuroprotection

  2025cites this paper
• Animal Venoms as Potential Source of Anticonvulsants

  2024cites this paper
• Changes in NMDA Receptor Function in Rapid Ischemic Tolerance: A Potential Role for Tri-Heteromeric NMDA Receptors

  2022cites this paper
• Peptide antagonists of NMDA receptors: Structure-activity relationships for potential therapeutics.

  2022cites this paper
• Reply to Comment on Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-d-aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro.

  2021cites this paper
• Post-translationally modified conopeptides: Biological activities and pharmacological applications.

  2021cites this paper
• DMV extrasynaptic NMDA receptors regulate caloric intake in rats

  2021cites this paper
• Toxinology of Marine Venomous Snails

  2021cites this paper
• Comment on Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-d-Aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro

  2021cites this paper
• Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-d-aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro.

  2020cites this paper
• BDNF increases synaptic NMDA receptor abundance by enhancing the local translation of Pyk2 in cultured hippocampal neurons

  2019cites this paper
• Conotoxins: Chemistry and Biology.

  2019cites this paper
• Toxins as tools: Fingerprinting neuronal pharmacology.

  2018cites this paper
• Peptide therapeutics from venom: Current status and potential.

  2017cites this paper
• Animal toxins for channelopathy treatment

  2017cites this paper
• Antagonistic action on NMDA/GluN2B mediated currents of two peptides that were conantokin-G structure-based designed

  2017influential citation
• Disulfide Bond and Topological Isomerization of the Conopeptide PNID: Disulfide Bonds with a Twist.

  2017cites this paper
• Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations

  2017cites this paper
• Discerning the Role of the Hydroxyproline Residue in the Structure of Conantokin Rl-B and Its Role in GluN2B Subunit-Selective Antagonistic Activity toward N-Methyl-d-Aspartate Receptors.

  2016cites this paper
• In the picture: disulfide-poor conopeptides, a class of pharmacologically interesting compounds

  2016cites this paper
• Prey-Capture Strategies of Fish-Hunting Cone Snails: Behavior, Neurobiology and Evolution

  2016cites this paper
• Regulation of synaptic transmission by BDNF : effects on NMDA receptor-mediated mEPSCs

  2016cites this paper
• Potencies and unblocking kinetic properties of antagonists at recombinant human NMDA receptors in a Xenopus oocytes model

  2015cites this paper
• Prey-Capture Strategies of Fish-Hunting Cone Snails: Behavior, Neurobiology and Evolution

  2015cites this paper
• NeuronsSpontaneous EPSCs in Cultured Cortical - Effect of Conantokin G on NMDA Receptor

  2015cites this paper
• 23-1 Mollusks–1

  2014cites this paper
• Conotoxins and Other Conopeptides

  2014cites this paper
• Conantokins: Developing pharmacology for differentiating N-methyl-D-aspartate receptor subtypes

  2014influential citation
• Synthetic conantokin peptides potently inhibit N‐methyl‐D‐aspartate receptor‐mediated currents of retinal ganglion cells

  2014cites this paper
• Conantokins Derived from the Asprella Clade Impart Con Rl -B, an NMDA Receptor Antagonist with a Unique Selectivity Profile for NR2B Subunits

  2014cites this paper
• Probing NMDA receptor GluN2A and GluN2B subunit expression and distribution in cortical neurons.

  2014cites this paper
• Conotoxin Gene Superfamilies

  2014cites this paper
• Conotoxins and their regulatory considerations.

  2014cites this paper
• From molecular phylogeny towards differentiating pharmacology for NMDA receptor subtypes.

  2014cites this paper
• Conotoxins: Modulators of Ion Channel and their Applications

  2014cites this paper
• 23-2 Mollusks–2

  2014cites this paper
• Incorporation of post-translational modified amino acids as an approach to increase both chemical and biological diversity of conotoxins and conopeptides

  2013cites this paper
• Incorporation of post-translational modified amino acids as an approach to increase both chemical and biological diversity of conotoxins and conopeptides

  2013cites this paper
• 6.5 Mechanosensory Transduction

  2012cites this paper
• Conantokins derived from the Asprella clade impart conRl-B, an N-methyl d-aspartate receptor antagonist with a unique selectivity profile for NR2B subunits.

  2012cites this paper
• Leptin Enhances NR2B-mediated NMDA Responses Via a MAPK-dependent Process in Cerebellar Granule Cells.

  2012cites this paper
• Opposing action of conantokin-G on synaptically and extrasynaptically-activated NMDA receptors.

  2012cites this paper
• GLUTAMATE RECEPTORS; FROM BASIC PHARMACOLOGY TO CLINICAL APPLICATIONS

  2012cites this paper
• Deciphering the molecular signaling cascade in neuronal death

  2011cites this paper
• CGX-1007 prevents excitotoxic cell death via actions at multiple types of NMDA receptors.

  2011cites this paper
• Ef fects of Intrahypocampal Administration of the BLMP-101 Peptide on a Spatial Memory Task in Wistar Rats

  2010cites this paper
• Specific determinants of conantokins that dictate their selectivity for the NR2B subunit of N-methyl-D-aspartate receptors.

  2010cites this paper
• Uso de una conantokina y anticuerpos policlonales para identificar la subunidad NR2B del receptor n-metil-d-aspartato The use of conantokin and polyclonal antibodies to identify the NR2B subunit of the n-methyl-d-aspartate receptor

  2010cites this paper
• Conjugation of peptides to the passivation shell of gold nanoparticles for targeting of cell-surface receptors.

  2010cites this paper
• Efectos de la aplicación intrahipocampal del péptido BLMP-101 sobre una tarea de memoria espacial en ratas Wistar

  2010cites this paper
• Conantokins inhibit NMDAR-dependent calcium influx in developing rat hippocampal neurons in primary culture with resulting effects on CREB phosphorylation.

  2010cites this paper
• NEUROTOXINS FROM INVERTEBRATES AS ALTERNATIVE THERAPEUTIC AGENTS AND TOOLS IN BASIC RESEARCH

  2009cites this paper
• The role of group I metabotropic glutamate receptors in neuronal excitotoxicity in alzheimer’s disease

  2009cites this paper
• BIOSENSORS: IMPLEMENTATION AND OUTLOOK IN THE CONTROL AND PROCESS QUALITY AND FOODSTUFFS

  2009cites this paper
• Chapter 36 – Biology and Pharmacology of Conotoxins

  2009cites this paper
• Ligands for ionotropic glutamate receptors.

  2009cites this paper
• Conantokins: From “sleeper” activity to drug development

  2009cites this paper
• Blockade of hindbrain NMDA receptors containing NR2 subunits increases sucrose intake.

  2009cites this paper
• Non-strict strand orientation of the Ca2+-induced dimerization of a conantokin peptide variant with sequence-shifted gamma-carboxyglutamate residues.

  2009cites this paper
• Neuroprotective and cardioprotective conopeptides: an emerging class of drug leads.

  2009cites this paper
• NMDA NR2 receptors participate in CCK-induced reduction of food intake and hindbrain neuronal activation.

  2009cites this paper
• Conantokin-Br from Conus brettinghami and selectivity determinants for the NR2D subunit of the NMDA receptor.

  2009cites this paper
• Studies on neuronal apoptoisis in primary forebrain cultures: Neuroprotective/anti-apoptotic action of NR2B NMDA antagonists

  2009cites this paper
• Cell-type Specific Development of NMDA Receptors in the Interneurons of Rat Prefrontal Cortex

  2009cites this paper
• Conotoxins: molecular and therapeutic targets.

  2009cites this paper
• 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.

  2009cites this paper
• Differences in excitatory transmission between thalamic and cortical afferents to single spiny efferent neurons of rat dorsal striatum

  2008cites this paper
• NR2B-selective conantokin peptide inhibitors of the NMDA receptor display enhanced antinociceptive properties compared to non-selective conantokins.

  2008cites this paper
• Conus venoms - a rich source of peptide-based therapeutics.

  2008cites this paper
• Novel Conantokins from Conus parius Venom Are Specific Antagonists of N-Methyl-D-aspartate Receptors*

  2007cites this paper
• Subtype-selective antagonism of N-methyl-D-aspartate receptor ion channels by synthetic conantokin peptides.

  2007influential citation
• Polymodal Regulation of NMDA Receptor-Channels

  2007cites this paper
• The molecular basis of conantokin antagonism of NMDA receptor function.

  2007cites this paper
• Effect of Conantokin G on NMDA receptor-mediated spontaneous EPSCs in cultured cortical neurons.

  2006influential citation
• Conotoxins down under.

  2006cites this paper
• NMDA receptor subunit‐dependent modulation by conantokin‐G and Ala(7)‐conantokin‐G

  2006influential citation
• Synaptic and extrasynaptic NMDA receptors in hippocampal neurons: regulation of nuclear shape and cell fate

  2006cites this paper
• Leptin enhances NR2B-mediated N-methyl-D-aspartate responses via a mitogen-activated protein kinase-dependent process in cerebellar granule cells.

  2006cites this paper
• New Horizons in the development of antiepileptic drugs: Innovative strategies.

  2006cites this paper
• Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice.

  2006cites this paper
• Modulation neuroprotectrice des activite du sous-type du recepteur nmda

  2006cites this paper
• Spontaneous EPSCs in Cultured Cortical Neurons Mediated − Effect of Conantokin G on NMDA Receptor

  2006influential citation
• Conotoxins: Therapeutic Potential and Application

  2006cites this paper
• Recent advances in the development of NR2B subtype-selective NMDA receptor antagonists.

  2006cites this paper
• NMDA receptor function: subunit composition versus spatial distribution

  2006influential citation
• N-methyl-D-aspartate receptor (NMDA) antagonists as potential pain therapeutics.

  2006cites this paper
• N-Methyl-D-aspartate Receptor Subtype Mediated Bidirectional Control of p38 Mitogen-activated Protein Kinase*

  2005cites this paper
• Antiepileptics and the treatment of neuropathic pain: evidence from animal models.

  2005cites this paper
• Effects of delayed intrathecal infusion of an NMDA receptor antagonist on ischemic injury and peri-infarct depolarizations.

  2005cites this paper
• N-methyl-D-aspartate Receptor Subtypes: Multiple Roles in Excitotoxicity and Neurological Disease

  2005cites this paper
• Ionotropic and metabotropic glutamate receptor structure and pharmacology

  2005cites this paper
• NR2B subtype-selective NMDA receptor antagonists: 2001 – 2004

  2005cites this paper
• NMDA antagonists and neuropathic pain--multiple drug targets and multiple uses.

  2005cites this paper
• The effects of alanine-substituted conantokin-G and ifenprodil on the human spermine-activated N-methyl-D-aspartate receptor.

  2005cites this paper
• Ginsenoside Rg3 antagonizes NMDA receptors through a glycine modulatory site in rat cultured hippocampal neurons.

  2004cites this paper
• The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on NMDA receptor-mediated EPSCs.

  2004cites this paper
• Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents in a mouse model of Huntington disease.

  2004influential citation
• Conantokins: peptide antagonists of NMDA receptors.

  2004cites this paper
• The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression.

  2004cites this paper