Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP


Bivalve molluscs, the primary vectors of paralytic shellfish poisoning (PSP) in humans, show marked inter-species variation in their capacity to accumulate PSP toxins (PSTs)1 which has a neural basis2,3. PSTs cause human fatalities by blocking sodium conductance in nerve fibres4,5. Here we identify a molecular basis for inter-population variation in PSP resistance within a species, consistent with genetic adaptation to PSTs. Softshell clams (Mya arenaria) from areas exposed to ‘red tides’ are more resistant to PSTs, as demonstrated by whole-nerve assays, and accumulate toxins at greater rates than sensitive clams from unexposed areas. PSTs lead to selective mortality of sensitive clams. Resistance is caused by natural mutation of a single amino acid residue, which causes a 1,000-fold decrease in affinity at the saxitoxin-binding site in the sodium channel pore of resistant, but not sensitive, clams. Thus PSTs might act as potent natural selection agents, leading to greater toxin resistance in clam populations and increased risk of PSP in humans. Furthermore, global expansion of PSP to previously unaffected coastal areas6 might result in long-term changes to communities and ecosystems.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Responses to PSTs in two M. arenaria populations.
Figure 2: Nerve response of toxin-free, individual clams to STX in vitro.
Figure 3: Mutation in the Na+ channel pore of resistant M. arenaria.
Figure 4: Blocking of WT and mutant Na+ channels by TTX and STX.


  1. Bricelj, V. M. & Shumway, S. E. Paralytic shellfish toxins in bivalve mollusks: occurrence, transfer kinetics, and biotransformation. Rev. Fish. Sci. 6, 315–383 (1998)

    CAS  Article  Google Scholar 

  2. Twarog, B. M., Hidaka, T. & Yamaguchi, H. Resistance to tetrodotoxin and saxitoxin in nerves of bivalve mollusks. Toxicon 10, 273–278 (1972)

    CAS  Article  Google Scholar 

  3. Twarog, B. M. in Proc. 2nd Int. Coral Reef Symp. Vol. 1 (eds Cameron, A. M. et al.) 505–512 (Barrier Reef Committee, Brisbane, 1974)

    Google Scholar 

  4. Narahashi, T. & Moore, J. W. Neuroactive agents and nerve membrane conductances. J. Gen. Physiol. 51, 93–101 (1968)

    CAS  Article  Google Scholar 

  5. Hille, B. Pharmacological modifications of the sodium channels of frog nerve. J. Gen. Physiol. 51, 199–219 (1968)

    CAS  Article  Google Scholar 

  6. Hallegraeff, G. M. in Manual on Harmful Marine Microalgae (eds Hallegraeff, G. M., Anderson, D. M. & Cembella, A. D.) 25–49 (UNESCO, Paris, 2003)

    Google Scholar 

  7. Fozzard, H. A. & Hanck, D. Structure and function of voltage-dependent sodium channels: comparison of brain II and cardiac isoforms. Physiol. Rev. 76, 887–926 (1996)

    CAS  Article  Google Scholar 

  8. Catterall, W. A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26, 13–25 (2000)

    CAS  Article  Google Scholar 

  9. Martin, J. L. & Richard, D. in Harmful and Toxic Algal Blooms (eds Yasumoto, T., Oshima, Y. & Fukuyo, Y.) 3–6 (International Oceanographic Commission of UNESCO, Paris, 1996)

    Google Scholar 

  10. Bricelj, V. M., Cembella, A. D., Laby, D., Shumway, S. E. & Cucci, T. L. in Harmful and Toxic Algal Blooms (eds Yasumoto, T., Oshima, Y. & Fukuyo, Y.) 405–408 (International Oceanographic Commission of UNESCO, Paris, 1996)

    Google Scholar 

  11. MacQuarrie, S. P. Inter- and Intra-population Variability in Behavioral and Physiological Responses of the Softshell Clam, Mya arenaria, to the PSP Toxin-producing Dinoflagellate, Alexandrium tamarense. Thesis, Dalhousie Univ. (2002)

    Google Scholar 

  12. Terlau, S. H. et al. Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II. FEBS Lett. 293, 93–96 (1991)

    CAS  Article  Google Scholar 

  13. Satin, J. et al. A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties. Science 256, 1202–1205 (1992)

    ADS  CAS  Article  Google Scholar 

  14. Sivilotti, L., Okuse, K., Akopian, A. N., Moss, S. & Wood, J. N. A single serine residue confers tetrodotoxin insensitivity on the rat sensory-neuron-specific sodium channel SNS. FEBS Lett. 409, 49–52 (1997)

    CAS  Article  Google Scholar 

  15. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet. 33 (Suppl.), 245–254 (2003)

    CAS  Article  Google Scholar 

  16. Auld, V. J. et al. A neutral amino acid change in segment IIS4 dramatically alters the gating properties of the voltage-dependent sodium channel. Proc. Natl Acad. Sci. USA 87, 323–327 (1990)

    ADS  CAS  Article  Google Scholar 

  17. Lipkind, G. & Fozzard, H. A. A structural model of the tetrodotoxin and saxitoxin binding site of the Na+ channel. Biophys. J. 66, 1–13 (1994)

    ADS  CAS  Article  Google Scholar 

  18. Kontis, K. J. & Goldin, A. L. Site-directed mutagenesis of the putative pore region of the rat IIA sodium channel. Mol. Pharmacol. 43, 635–644 (1993)

    CAS  PubMed  Google Scholar 

  19. Kvitek, R. G. & Beitler, M. K. Relative insensitivity of butter clam neurons to saxitoxin: a pre-adaptation for sequestering paralytic shellfish poisoning toxins as a chemical defense. Mar. Ecol. Prog. Ser. 69, 47–54 (1991)

    ADS  Article  Google Scholar 

  20. Liu, M.-Y., Bull, D. L. & Plapp, F. W. Jr Effects of exposure to cypermethrin on saxitoxin binding in susceptible and pyrethroid-resistant houseflies. Arch. Insect Biochem. Physiol. 37, 73–79 (1998)

    CAS  Article  Google Scholar 

  21. He, H. et al. Identification of a point mutation in the para-type sodium channel gene from a pyrethroid-resistant cattle tick. Biochem. Biophys. Res. Commun. 261, 558–561 (1999)

    CAS  Article  Google Scholar 

  22. Yamashita, M.-Y. et al. Binding properties of 3H-PbTx-3 and 3H-saxitoxin to brain membranes and to skeletal muscle membranes of puffer fish Fugu pardalis and the primary structure of a voltage-gated Na+ channel α-subunit (fMNa1) from skeletal muscle of F. pardalis. Biochem. Biophys. Res. Commun. 267, 403–412 (2000)

    Article  Google Scholar 

  23. Geffeney, S., Brodie, E. D. Jr, Ruben, P. C. & Brodie, E. D. III Mechanisms of adaptation in a predator-prey arms race: TTX-resistant sodium channels. Science 297, 1336–1339 (2002)

    ADS  CAS  Article  Google Scholar 

  24. Bricelj, V. M., Lee, J. H. & Cembella, A. D. Influence of dinoflagellate cell toxicity on uptake and loss of paralytic shellfish toxins in the northern quahog, Mercenaria mercenaria (L.). Mar. Ecol. Prog. Ser. 74, 33–46 (1991)

    ADS  CAS  Article  Google Scholar 

  25. Oshima, Y. in Manual on Harmful Marine Microalgae (eds Hallegraeff, G. M., Anderson, D. M. & Cembella, A. D.) 81–94 (International Oceanographic Commission Manuals and Guides 33, UNESCO, Paris, 1995)

    Google Scholar 

  26. Storici, L., Lewis, K. & Resnick, M. A. In-vivo site-directed mutagenesis using oligonucleotides. Nature Biotechnol. 19, 773–776 (2001)

    CAS  Article  Google Scholar 

  27. Linford, N. J., Cantrell, A. R., Qu, Y., Scheuer, T. & Catterall, W. A. Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel. Proc. Natl Acad. Sci. USA 95, 13947–13952 (1998)

    ADS  CAS  Article  Google Scholar 

Download references


We thank B. M. Twarog, whose seminal work in the 1970s inspired this study, for conducting the initial nerve tests; P. Chang for participating in the burrowing experiment; M. Quilliam and the IMB analytical toxins group for providing STX for nerve tests; and E. M. Sharp and M. Iszard for technical assistance. This work was supported by a US NOAA-ECOHAB grant to V.L.T. and V.M.B., a NOAA-ECOHAB grant to L.C., V.L.T. and V.M.B., and an NIH research grant to W.A.C.

Author information

Authors and Affiliations


Corresponding author

Correspondence to V. Monica Bricelj.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

Illustrates voltage-dependent electrophysiological properties (activation and inactivation of the Na+ current) of transfected wild-type and mutant Na+ channels. (DOC 567 kb)

Supplementary Discussion

Includes a discussion of differences in the sensitivity to toxins between Mya arenaria nerves and transfected Na+ channels, and references cited therein. (DOC 27 kb)

Supplementary Methods

Describes the methods of clam nucleic acid extraction, production of cDNA, isolation of Na+ channel specific fragments, determination of the Na+ channel sequence from individual clams, and the construction of Na+ channel mutations, including cited references. (DOC 40 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bricelj, V., Connell, L., Konoki, K. et al. Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP. Nature 434, 763–767 (2005).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing