Conantokin-T, a naturally peptidic NMDA receptor antagonist



Conantokin-T (Gly-Glu-Gla-Gla-Tyr-Gln-Lys-Met-Leu-Gla-Asn-Leu-Arg-Gla-Ala-Glu-Val-Lys-Asn-Ala-NH2), a 21-amino acid peptide which induces sleep-like symptoms in young mice is purified from the venom of the fish-hunting cone snail, Conus tulipa. This peptide is structurally unique. In contrast to the well characterized conotoxins from Conus venoms, it does not contain disulfide bonds, but contain 5 residues of the unusual modified amino acid γ-carboxyglutamate (Gla). Conantokin-T has N-methyl-D-aspartate (NMDA) antagonist activity by inhibiting NMDA receptor-mediated calcium influx in central nervous system neurons.

Biological Activity

Conantokin-T is a naturally occurring peptidic compounds that possess N-methyl-D-aspartate receptor antagonist activity. This antagonism derives from a noncompetitive inhibitory effect of the polyamine agonist site of the receptor. The physiological responses elicit following intracranial injections in mice include a sleep-like state in neonatal mice and a hyperactive response in older animals. The 4 Gla residues in conantokins-T are key elements for the biological activity of this peptide. Gla residues are originally identified in the vitamin K-dependent blood-clotting factors including prothrombin. Subsequently they are found in other vertebrate proteins such as osteocalcin (calcium-binding protein) and have been implicated in Ca2+ binding. The discovery of Gla residues in several Conus peptides has established that this posttranslational modification has a much wider phylogenetic distribution than previously thought. In fura-2 fluorescence assays on cere granule cells demonstrate that conantokin-T produces a partial antagonism of NMDA receptor function, with an apparent IC50 of 2 μM. This partial antagonism can reflect agonist or allosteric inhibitory action or specificity of conantokin-T for only a subset of NMDA receptor-ionophore complexes


The NMDA subtype of glutamate receptor is a ligand-gated ion channel that displays high permeability for Ca2+. The marked excitotoxicity of glutamate is generally regarded as ascribable to its persistent interaction with the NMDA receptor (NMDAR), resulting in the establishment of neurodegenerative glutamatergic loops defined by uncontrolled elevations of intracellular Ca2+, followed by cell lysis and death. Because the Ca2+-mediated neuronal cell death, which is attendant to both acute (e.g. ischemia) and chronic (e.g. epilepsy, Parkinson's disease) neurodegenerative disorders, can be ameliorated by antagonists specific for the NMDAR.


Haack, J. A., Rivier, J., Parks, T. N., Mena, E. E., Cruz, L. J., & Olivera, B. M. (1990). Conantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-d-aspartate antagonist activity. Journal of Biological Chemistry, 265(11), 6025-6029.

Prorok, M., & Castellino, F. J. (1998). Thermodynamics of Binding of Calcium, Magnesium, and Zinc to theN-Methyl-D-aspartate Receptor Ion Channel Peptidic Inhibitors, Conantokin-G and Conantokin-T. Journal of Biological Chemistry, 273(31), 19573-19578.

Skjærbæk, N., Nielsen, K. J., Lewis, R. J., Alewood, P., & Craik, D. J. (1997). Determination of the solution structures of conantokin-G and conantokin-T by CD and NMR spectroscopy. Journal of Biological Chemistry, 272(4), 2291-2299.

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