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A study on mechanisms of toxic actions of ciguatoxins: existence of functional relationship between CTX3C and charged residues of voltage sensors in Nav1.4 sodium channel

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Abstract

Ciguatoxins, a group of virulent marine toxins, are bound to "site 5" inside voltage-dependent sodium channels and alter their kinetics dramatically; this is probably responsible for clinical symptoms of ciguatoxin poisoning or ciguatera. Although ciguatoxins are known to affect the voltage dependency of both activation and inactivation kinetics, site 5 has not been functionally clarified. This study, therefore, targeted putative voltage sensors as a receptor for ciguatoxins. We constructed mutants, in which 1 of 23 basic residues was substituted with glutamine in the S4 segment for each of four domains. We then examined the effects of a synthetic ciguatoxin congener CTX3C on these mutants. Notably, the suppressive effect of CTX3C on the sodium current (I Na) amplitude of domain 2 mutants, which carried a mutation in the basic S4 residue of domain 2, was either reduced or eliminated. Kinetic analyses of domain 2 mutants in comparison with those of the wild type and other mutants revealed that the negative shift of the steady-state inactivation curve (V 1/2inactΔ) was significantly decreased. The resistance of domain 2 mutants to CTX3C in terms of changes in V 1/2inact is suggested to be closely related to resistance to the suppressive effect of CTX3C on the I Na amplitude. This is the first report to demonstrate the existence of a functional relationship between a ciguatoxin congener and voltage sensor segments in domain 2 of the α-subunit of voltage-dependent sodium channels, although further studies are needed to locate a ciguatoxin receptor.

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Acknowledgments

This work was supported by a Grant-in-Aid for Specially Promoted Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. We thank Ms. C. Kondo for technical assistance.

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Authors and Affiliations

  1. Department of Physical Therapy, Faculty of Health Sciences, Hiroshima International University, 555-36 Gakuendai, Kurose, Higashi-Hiroshima, 739-2695, Japan

    Kaoru Yamaoka

  2. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Masayuki Inoue

  3. Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, Japan

    Masahiro Hirama

Authors
  1. Kaoru Yamaoka
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  2. Masayuki Inoue
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  3. Masahiro Hirama
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Corresponding author

Correspondence to Kaoru Yamaoka.

Additional information

Part of this study was presented at the 29th Annual Meeting of Japanese Association of Forensic Toxicology, Tokyo, as part of the symposium “Research and Analysis on Marine Neurotoxins at the Forefront”.

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Yamaoka, K., Inoue, M. & Hirama, M. A study on mechanisms of toxic actions of ciguatoxins: existence of functional relationship between CTX3C and charged residues of voltage sensors in Nav1.4 sodium channel. Forensic Toxicol 29, 125–131 (2011). https://doi.org/10.1007/s11419-011-0113-6

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  • DOI: https://doi.org/10.1007/s11419-011-0113-6

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