Skip to main content
SpringerLink
Log in

Molecular mechanism of scorpion neurotoxins acting on sodium channels

Insight into their diverse selectivity

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Scorpion toxins that affect sodium channel gating traditionally are divided into α- and β-classes. They show vast diversity in their selectivity for phyletic- or isoform-specific sodium channels. This article discusses the molecular mechanism of the selectivity. Moreover, a phylogenetic tree of scorpion toxins has been constructed, which, together with the worldwide distribution of toxins and the zoogeographic dispersion of the studied genera, offers an insight into the evolution of diverse scorption toxins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Blumenthal K. and Seibert A. (2003) Voltage-gated sodium channel toxins: poisons, probes, and future promise. Cell Biochem. Biophys. 38, 215–238.

    Article  PubMed  CAS  Google Scholar 

  2. Cestele S. and Catterall W. A. (2000) Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 82, 883–892.

    Article  PubMed  CAS  Google Scholar 

  3. Froy O. and Gurevitz M. (2003) New insight on scorpion divergence inferred from comparative analysis of toxin structure, pharmacology and distribution. Toxicon 42, 549–555.

    Article  PubMed  CAS  Google Scholar 

  4. Couraud F., Jover E., Dubois J. M., and Rochat H. (1982) Two types of scorpion receptor sites, one related to the activation, the other to the inactivation of the action potential sodium channel. Toxicon 20, 9–16.

    Article  PubMed  CAS  Google Scholar 

  5. Possani L. D., Becerril B., Delepierre M., and Tytgat J. (1999) Scorpion toxins specific for Na+-channels. Eur. J. Biochem. 264, 287–300.

    Article  PubMed  CAS  Google Scholar 

  6. Gordon D. and Gurevitz M. (2003) The selectivity of scorpion alpha-toxins for sodium channel subtypes is determined by subtle variations at the interacting surface. Toxicon 41, 125–128.

    Article  PubMed  CAS  Google Scholar 

  7. Li Y. J. and Ji Y. H. (2000) Binding characteristics of BmKI, an alpha-like scorpion neurotoxic polypeptide, on cockroach nerve cord synaptosomes. J. Pept. Res. 56, 195–200.

    Article  PubMed  CAS  Google Scholar 

  8. Gordon D., Ilan N., Zilberberg N., Gilles N., Urbach D., Cohen L, et al. (2003) An “Old World” scorpion beta-toxin that recognizes both insect and mammalian sodium channels. Eur. J. Biochem. 270, 2663–2670.

    Article  PubMed  CAS  Google Scholar 

  9. Li Y. J., Liu Y., and Ji Y. H. (2000) BmK AS: new scorpion neurotoxin binds to distinct receptor sites of mammal and insect voltage-gated sodium channels. J. Neurosci. Res. 61, 541–548.

    Article  PubMed  CAS  Google Scholar 

  10. Lopreato G. F., Lu Y., Southwell A., et al. (2001) Evolution and divergence of sodium channel genes in vertebrates. Proc. Natl. Acad. Sci. USA 98, 7588–7592.

    Article  PubMed  CAS  Google Scholar 

  11. Rogers J. C., Qu Y., Tanada T. N., Scheuer T., and Catterall W. A. (1996) Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit. J. Biol. Chem. 271, 15,950–15,962.

    CAS  Google Scholar 

  12. Benzinger G. R., Kyle J. W., Blumenthal K. M., and Hanck D. A. (1998) A specific interaction between the cardiac sodium channel and site-3 toxin anthopleurin B. J. Biol. Chem. 273, 80–84.

    Article  PubMed  CAS  Google Scholar 

  13. Leipold E., Lu S., Gordon D., Hansel A., and Heinemann S. H. (2004) Combinational interaction of scorpon toxins Lqh-2, Lqh-3, and Lqh-aIT with sodium channel receptor size-3. Mol. Pharmacol. 65, 685–691.

    Article  PubMed  CAS  Google Scholar 

  14. Gilles N., Chen H., Wilson H., et al. (2000) Scorpion α-and α-like toxins differentially interact with sodium channels in mammalian CNS and periphery. Eur. J. Neurosci. 12, 2823–2832.

    Article  PubMed  CAS  Google Scholar 

  15. Chen H., Gordon D., and Heinemann S. (2000) Modulation of cloned skeletal muscle sodium channel by the scorpion toxins Lqh II, Lqh III and LqhaIT. Pflügers Arch. 439, 423–432.

    Article  PubMed  CAS  Google Scholar 

  16. Chen H. and Heinemann S. H. (2001) Interaction of scorpion α-toxins with cardiac sodium channels: binding properties and enhancement of slow inactivation. J. Gen. Physiol. 117, 505–518.

    Article  PubMed  CAS  Google Scholar 

  17. Hamon A., Gilles N., Sautiere P., et al. (2002) Characterization of scorpion alpha-like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus. Eur. J. Biochem. 269, 3920–3933.

    Article  PubMed  CAS  Google Scholar 

  18. Gilles N., Blanchet B., Shichor I., et al. (1999) A scorpion α-like toxin active on insects and mammals reveals an unexpected specificity and distribution of sodium channel subtypes in rat brain neurons. J. Neurosci. 19, 8730–8739.

    PubMed  CAS  Google Scholar 

  19. Cestele S., Stankiewicz M., Mansuelle P., et al. (1999) Scorpion α-like toxins, toxic to both mammals and insects, differentially interact with receptor site 3 on voltage-gated sodium channels in mammals and insects. Eur. J. Neurosci. 11, 975–985.

    Article  PubMed  CAS  Google Scholar 

  20. Chen H., Lu S-Q., Leipold E., Gordon D., Hansel A., and Heinemann S. H. (2002) Differential sensitivity of sodium channels from the central and peripheral nervous system to the scorpion toxins Lqh-2 and Lqh-3. Eur. J. Neurosci. 16, 767–770.

    Article  PubMed  Google Scholar 

  21. Gordon D., Merrick D., Auld V., et al. (1987) Tissue-specific expression of the RI and RII sodium channel subtypes. Proc. Natl. Acad. Sci. USA 84, 8682–8686.

    Article  PubMed  CAS  Google Scholar 

  22. Gordon D., Gilles N., Bertrand D., et al. (2002) Scorpion toxins differentiating among neuronal sodium channel subtypes: nature’s guide for design of selective drugs. In: Menez A., ed. Perspectives in Molecular Toxinology, Wiley, Chichester, England, pp. 215–238.

    Google Scholar 

  23. Tejedor F. J. and Catterall W. A. (1988) A site of covalent attachment of alpha-scorpion toxin derivatives in domain I of the sodium channel alpha subunit. Proc. Natl. Acad. Sci. USA 85, 8742–8746.

    Article  PubMed  CAS  Google Scholar 

  24. Thomsen W. J. and Catterall W. A. (1989) Localization of the receptor site for α-scorpion toxins by antibodies mapping: implications for sodium channel topology. Proc. Natl. Acad. Sci. USA 86, 10,161–10,165.

    Article  CAS  Google Scholar 

  25. Housset D., Habersetzer-Rochat C., Astier J., and Fontecilla-Camps J. C. (1994) Crystal structure of toxin II from the scorpion Androctonus australis Hector refined at 1.3 Å resolution. J. Mol. Biol. 238, 88–103.

    Article  PubMed  CAS  Google Scholar 

  26. Jablonsky M. J., Watt D. D., and Krishna N. R. (1995) Solution structure of an old world-like neurotoxin from the venom of the new world scorpion Centruroides sculpturatus Ewing. J. Mol. Biol. 248, 449–458.

    PubMed  CAS  Google Scholar 

  27. Li H. M., Wang D.-C., Zeng Z.-H., Jin L., and Hu R. Q. (1996) Crystal structure of an acidic neurotoxin from scorpion Buthus martensii Karsch at 1.85 Å. J. Mol. Biol. 261, 415–431.

    Article  PubMed  CAS  Google Scholar 

  28. Landon C., Sodano P., Cornet B., et al. (1997) Refined solution structure of the anti-mammal and anti-insect LqqIII scorpion toxin: comparison with other scorpion toxins. Proteins 28, 360–374.

    Article  PubMed  CAS  Google Scholar 

  29. Tugarinov V., Kustanovich I., Zilberberg N., Gurevitz M., and Anglister J. (1997) Solution structures of a highly insecticidal recombinant scorpion alpha- toxin and a mutant with increased activity. Biochemistry 36, 2414–2424.

    Article  PubMed  CAS  Google Scholar 

  30. He X.-L. Li H.-M., Zeng Z.-H., Liu X-Q., Wang M., and Wang D.-C. (1999) Crystal structures of two α-like scorpion toxins: non-proline cis peptide bonds and implications for new binding site selectivity on the sodium channel. J. Mol. Biol. 292, 125–135.

    Article  PubMed  CAS  Google Scholar 

  31. Krimm I., Gilles N., Sautiere P., et al. (1999) NMR structures and activity of a novel alphalike toxin from the scorpion Leiurus quinques-triatus hebraeus. J. Mol. Biol. 285, 1749–1763.

    Article  PubMed  CAS  Google Scholar 

  32. He X.-L., Deng J. P., Wang M., Zhang Y., and Wang D.-C. (2000) Structure of a new neurotoxin from the scorpion Buthus martensii Karsch at 1.76 Å. Acta Crystallogr. 56, 25–33.

    Article  CAS  Google Scholar 

  33. Wang C. G., Gilles N., Hamon A., et al. (2003) Exploration of the functional site of a scorpion alpha-like toxin by site-directed mutagenesis. Biochemistry 42, 4699–4708.

    Article  PubMed  CAS  Google Scholar 

  34. Marcotte P., Chen L-Q., Kallen R. G., and Chahnin M. (1997) Effects of Tityus serrulatus scorpion toxin gamma on voltage-gated Na+ channels. Cir. Res. 80, 363–369.

    CAS  Google Scholar 

  35. Cestele S., Qu Y., Rogers J. C., Rochat H., and Catterall W. A. (1998) Voltage sensor trapping: enhanced activation of sodium channels by β-scorpion toxin bound to the S3–S4 loop in domain II. Neuron 21, 919–931.

    Article  PubMed  CAS  Google Scholar 

  36. Shichor I., Zlotkin E., Ilan N., et al. (2002) Domain 2 of Drosophila para voltage-gated sodium channel confers insect properties to a rat brain channel. J. Neurosci. 22, 4364–4371.

    PubMed  CAS  Google Scholar 

  37. De Lima M. E., Martin-Eauclaire M. F., Hue B., Loret E., Diniz C. R., and Rochat H. (1989) On the binding of two scorpion toxins to the central nervous system of the cockroach Periplaneta. Americana. Insect. Biochem. 19, 413–422.

    Google Scholar 

  38. Zlotkin E., Kadouri D., Gordon D., Pelhate M., Martin M. F., and Rochat H. (1985) An excitatory and a depressant insect toxin from scorpion venom both affect sodium conductance and possess a common binding site. Arch. Biochem. Biophys. 240, 877–887.

    Article  PubMed  CAS  Google Scholar 

  39. Gordon D., Jover E., Couraud F., and Zlotkin E. (1984) The binding of the insect selective neurotoxin (AaIT) form the venom to locust synaptosomal membranes. Biochem. Biophys. Acta 778, 349–358.

    Article  CAS  Google Scholar 

  40. Zlotkin E., Eitan M., Bindokas V. P., et al. (1991) Functional duality and structural uniqueness of depressant insect-delective neurotoxins. Biochemistry 30, 4814–4821.

    Article  PubMed  CAS  Google Scholar 

  41. Gordon D., Moskowitz H., Warmer C., Catterall W. A., and Zlotkin E. (1992) Localization of the receptor sites for insect-selective toxins on sodium channels by site-directed mutagenesis. Biochemistry 31, 7622–7628.

    Article  PubMed  CAS  Google Scholar 

  42. Cestèle S., Kopeyan C., Oughideni R., Mansuelle P., Granier C., and Rochat H. (1997) Biochemical and pharmacological characterization of a depressant insect toxin from the venom of the scorpion Buthacus arenicola. Eur. J. Biochem. 243, 93–99.

    Article  PubMed  Google Scholar 

  43. Li Y-J., Tan Z-Y., and Ji Y-H. (2000) The binding of BmK IT2, a depressant insect-selective scorpion toxin on mammal and insect sodium channels. Neurosci. Res. 38, 257–264.

    Article  PubMed  CAS  Google Scholar 

  44. Loret E. P., Martin-Eauclaire M. F., Mansuelle P., Sampieri F., Granier C., and Rochat H. (1991) An anti-insect toxin purified from the scorpion Androctonus australis Hector also acts on the alpha- and beta-sites of the mammalian sodium channel: sequence and circular dichroism study. Biochemistry 30, 633–640.

    Article  PubMed  CAS  Google Scholar 

  45. Ye J. G., Wang C. Y., Li Y. J., et al. (2000) Purification, cDNA cloning and function assessment of BmK abT, a unique component from the Old World scorpion species. FEBS Lett. 479, 136–140.

    Article  PubMed  CAS  Google Scholar 

  46. Corona M., Coronas F. V., Merino E., et al. (2003) A novel class of peptide found in scorpion venom with neurodepressant effects in peripheral and central nervous system of the rat. Biochim Biophys Acta 1649, 58–67.

    PubMed  CAS  Google Scholar 

  47. Meves H., Simard J. M., and Watt D. D. (1984) Biochemical and electrophysiological characteristics of toxins isolated from the venom of the scorpion Centruroides sculpturatus. J. Physiol. (Paris) 79, 185–191.

    CAS  Google Scholar 

  48. Zhao B., Carson M., Ealick S. E., and Bugg C. E. (1992) Structure of scorpion toxin Variant-3 at 1.2 Å resolution. J. Mol. Biol. 227, 239–252.

    Article  PubMed  CAS  Google Scholar 

  49. Lee W., Jablonsky M. J., Watt D. D., and Krishna N. R. (1994) Proton nuclear magnetic resonance and distance geometry/simulated annealing studies on the variant-1 neurotoxin from the new world scorpion Centruroides sculpturatus Ewing. Biochemistry 33, 2468–2475.

    Article  PubMed  CAS  Google Scholar 

  50. Cook W. J., Zell A., Watt D. D., and Ealick S. E. (2002) Structure of variant 2 scorpion toxin from Centruroides sculpturatus Ewing. Protein Sci. 11, 479–486.

    Article  PubMed  CAS  Google Scholar 

  51. Darbon H., Weber C., and Braun W. (1991) Two-dimensional 1H nuclear magnetic resonance study of AaH IT, an anti-insect toxin from the scorpion Androctonus australis Hector. Sequential resonance assignments and folding of the polypeptide chain. Biochemistry 30, 1836–1845.

    Article  PubMed  CAS  Google Scholar 

  52. Oren D. A., Froy O., Amit E., Kleinberger-Doron N., Gurevitz M., and Shaanan B. (1998) An excitatory scorpion toxin with a distinctive feature: an additional alpha helix at the C terminus and its implications for interaction with insect sodium channels. Structure 6, 1095–1103.

    Article  PubMed  CAS  Google Scholar 

  53. Polikarpov I., Junior M. S. M., Marangoni S., Toyama M. H., and Teplyakov A. (1999) Crystal structure of neurotoxin Ts1 from Tityus serrulatus provides insights into the specificity and toxicity of scorpion toxins. J. Mol. Biol. 290, 175–184.

    Article  PubMed  CAS  Google Scholar 

  54. Pintar A., Possani L. D., and Delepierre M. (1999) Solution structure of toxin 2 from Centruroides noxius Hoffmann, a β-scorpion neurotoxin acting on sodium channels. J. Mol. Biol. 287, 359–367.

    Article  PubMed  CAS  Google Scholar 

  55. Froy O., Zilberberg N., Gordon D., et al. (1999) The putative bioactive surface of insect-selective scorpion excitatory neurotoxins. J. Biol. Chem. 274, 5769–5776.

    Article  PubMed  CAS  Google Scholar 

  56. Cohen L., Karbat I., Gilles N., et al. (2004) Dissection of the functional surface of an anti-insect excitatory toxin illuminates a putative “hot spot” common to all scorpion beta-toxins affecting Na+ channels. J. Biol. Chem. 279, 8206–8211.

    Article  PubMed  CAS  Google Scholar 

  57. Inceoglu B., Lango J., Wu J., Hawkins P., Southern J., and Hammock B. D. (2001) Isolation and characterization of a novel type of neurotoxic peptide from the venom of the South African scorpion Parabuthus transvaalicus (Buthidae). Eur. J. Biochem. 268, 5407–5413.

    Article  PubMed  CAS  Google Scholar 

  58. Inceoglu A. B., Hayashida Y., Lango J., Ishida A. T., and Hammock B. D. (2002) A single charged surface residue modifies the activity of ikitoxin, a beta-type Na+ channel toxin from Parabuthus transvaalicus. Eur. J. Biochem. 269, 5369–5376.

    Article  PubMed  CAS  Google Scholar 

  59. Fet V., Gantenbein B., Gromov A. V., Lowe G., and Lourenço W. R. (2003) The first molecular phylogeny of Buthidae (Scorpiones) Euscorpius—Occasional Publications in Scorpiology 4, 1–12.

    Google Scholar 

  60. Goudet C., Chi C. W., and Tytgat J. (2002) An overview of toxins and genes from the venom of the Asian scorpion Buthus martensi Karsch. Toxicon 40, 1239–1258.

    Article  PubMed  CAS  Google Scholar 

  61. Olamendi-Portugal T., Garcia B. I., Lopez-Gonzalez I., et al. (2002) Two new scorpion toxins that target voltage-gated Ca2+ and Na+ channels. Biochem. Biophys. Res. Commun. 299, 562–568.

    Article  PubMed  CAS  Google Scholar 

  62. Shunyi Z., Frank B., and Tytgat J. (2004) Adaptive evolution of scorpion sodium channel toxins. J. Mol. Evol., 58, 143–153.

    Google Scholar 

  63. Ceard B., Martin-Eauclaire M., and Bougis P.E. (2001) Evidence for a position-specific deletion as an evolutionary link between long- and short-chain scorpion toxins. FEBS Lett. 494, 246–248.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Key Laboratory of Neurobiology, Institute of Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China

    Xiao-Pan Zuo & Yong-Hua Ji

  2. School of Life Sciences, Shanghai University, China

    Yong-Hua Ji

Authors
  1. Xiao-Pan Zuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong-Hua Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong-Hua Ji.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zuo, XP., Ji, YH. Molecular mechanism of scorpion neurotoxins acting on sodium channels. Mol Neurobiol 30, 265–278 (2004). https://doi.org/10.1385/MN:30:3:265

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:30:3:265

Index Entries

Search

Navigation