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Synergistic and antagonistic interactions between tetrodotoxin and ¿-conotoxin in blocking voltage-gated sodium channels

Journal Article


Abstract


  • Tetrodotoxin (TTX) is the quintessential ligand of voltage-gated sodium channels (NaVs). Like TTX, μ-conotoxin peptides are pore blockers, and both toxins have helped to define the properties of neurotoxin receptor Site 1 of NaVs. Here, we report unexpected results showing that the recently discovered μ-conotoxin KIIIA and TTX can simultaneously bind to Site 1 and act in concert. Results with saturating concentrations of peptide applied to voltage-clamped Xenopus oocytes expressing brain NaV1.2, and single-channel recordings from brain channels in lipid bilayers, show that KIIIA or its analog, KIIIA[K7A], block partially, with a residual current that can be completely blocked by TTX. In addition, the kinetics of block by TTX and peptide are each affected by the prior presence of the other toxin. For example, bound peptide slows subsequent binding of TTX (an antagonistic interaction) and slows TTX dissociation when both toxins are bound (a synergistic effect on block). The overall functional consequence resulting from the combined action of the toxins depends on the quantitative balance between these opposing actions. The results lead us to postulate that in the bi-liganded NaV complex, TTX is bound between the peptide and the selectivity filter. These observations refine our view of Site 1 and open new possibilities in NaV pharmacology. ©2009 Landes Bioscience.

Publication Date


  • 2009

Citation


  • Zhang, M. M., McArthur, J. R., Azam, L., Bulaj, G., Olivera, B. M., French, R. J., & Yoshikami, D. (2009). Synergistic and antagonistic interactions between tetrodotoxin and ¿-conotoxin in blocking voltage-gated sodium channels. Channels, 3(1), 32-38. doi:10.4161/chan.3.1.7500

Scopus Eid


  • 2-s2.0-66149151034

Start Page


  • 32

End Page


  • 38

Volume


  • 3

Issue


  • 1

Abstract


  • Tetrodotoxin (TTX) is the quintessential ligand of voltage-gated sodium channels (NaVs). Like TTX, μ-conotoxin peptides are pore blockers, and both toxins have helped to define the properties of neurotoxin receptor Site 1 of NaVs. Here, we report unexpected results showing that the recently discovered μ-conotoxin KIIIA and TTX can simultaneously bind to Site 1 and act in concert. Results with saturating concentrations of peptide applied to voltage-clamped Xenopus oocytes expressing brain NaV1.2, and single-channel recordings from brain channels in lipid bilayers, show that KIIIA or its analog, KIIIA[K7A], block partially, with a residual current that can be completely blocked by TTX. In addition, the kinetics of block by TTX and peptide are each affected by the prior presence of the other toxin. For example, bound peptide slows subsequent binding of TTX (an antagonistic interaction) and slows TTX dissociation when both toxins are bound (a synergistic effect on block). The overall functional consequence resulting from the combined action of the toxins depends on the quantitative balance between these opposing actions. The results lead us to postulate that in the bi-liganded NaV complex, TTX is bound between the peptide and the selectivity filter. These observations refine our view of Site 1 and open new possibilities in NaV pharmacology. ©2009 Landes Bioscience.

Publication Date


  • 2009

Citation


  • Zhang, M. M., McArthur, J. R., Azam, L., Bulaj, G., Olivera, B. M., French, R. J., & Yoshikami, D. (2009). Synergistic and antagonistic interactions between tetrodotoxin and ¿-conotoxin in blocking voltage-gated sodium channels. Channels, 3(1), 32-38. doi:10.4161/chan.3.1.7500

Scopus Eid


  • 2-s2.0-66149151034

Start Page


  • 32

End Page


  • 38

Volume


  • 3

Issue


  • 1