Molecular biology of scorpion toxins active on potassium channels


Peptidyl scorpion toxins are known to block diverse types of K+ channels with high affinity and, thus, can be used as powerful tools to study the physiological role of the ionic selectivity, and the architecture of the pore-region of this class of channels. Yet, diversity among K+ channels is large and there has been a profusion of research for new selective ligands in order to elucidate their mechanisms of action and pharmacology significance. Scorpion toxins active on K+ channels are short polypeptides of about 30 to 40 amino acid residues, cross-linked by three or four disulfide bridges. They display a high degree of primary sequence homologies. 1H Nuclear Magnetic Resonance (NMR) analysis has demonstrated that these toxins are composed of an α-helix and a two-stranded antiparallel β-sheet, linked by two disulfide bridges. This structural motif is also found in the insect defensins. A 370 bp cDNA encoding the Kaliotoxin 2 (KTX2) precursor (a 37 amino acid residues peptide purified from the North African scorpion Androctonus australis and acting as a high affinity blocker of K+ channels) was obtained by PCR amplification and the organization of the KTX2 precursor depicted. This precursor is composed of a signal peptide followed by the mature toxin. The transcriptional unit and the promotor region of the gene encoding KTX2 was then amplified from the genomic DNA of Androctonus australis and its sequence determined. A single intron of 87 bp, located close to the region encoding the C-terminal part of the signal peptide, was found. Its A+T content was particularly high (up to 86%). The transcription unit of the gene was 390 bp long. Regulatory consensus sequences were identified. The genes of scorpion ‘short’ toxins active on K+ channels are organized similarly to those of the scorpion ‘long’ toxins active on Na+ channels and not like those of structurally related insect defensins, which are intronless.

This is a preview of subscription content, access via your institution.


  1. 1.

    Chicci, G.G., Gimenez-Gallego, G., Ber, E., Garcia, M.L., Winquist, R. and Cascieri, M.A., J. Biol. Chem., 263 (1988) 10192.

    Google Scholar 

  2. 2.

    Auguste, P., Hugues, M., Graves, B., Gesquiers, J. C., Maes, P., Tartar, A., Romey, G., Schweitz, H. and Lazdunsky, M., J. Biol. Chem., 265 (1990) 4753.

    Google Scholar 

  3. 3.

    Zerrouk, H., Mansuelle, P., Benslimane, A., Rochat, H. and Martin-Eauclaire, M.-F., FEBS Lett., 320 (1993) 189.

    Google Scholar 

  4. 4.

    Zerrouk, H., Laraba-Djebari, F., Fremont, V., Meki, A., Darbon, H., Mansuelle, P., Oughideni, R., Van Rietschtoten, J., Rochat, H. and Martin-Eauclaire, M.-F., Int. J. Pept. Protein Res., 48 (1996) 514.

    Google Scholar 

  5. 5.

    Romi-Lebrun, R., Martin-Eauclaire, M.-F., Escoubas, P., Wu, F.Q., Lebrun, B., Hisada, M. and Nakajima, T., Eur. J. Biochem., 245 (1997) 457.

    Google Scholar 

  6. 6.

    Legros, C., Oughideni, R., Darbon, H., Rochat, H., Bougis, P.E. and Martin-Eauclaire, M.-F., FEBS Lett., 390 (1996) 81.

    Google Scholar 

  7. 7.

    Olamendi-Portugal, T., Gomez-Lagunas, F., Gurrola, G.B. and Possani, L.D., Biochem. J., 315 (1996) 977.

    Google Scholar 

  8. 8.

    Kharrat, R., Mansuelle, F., Sampieri, F., Crest, M., Oughideni, R., Van Rietschoten, J. and Martin-Eauclaire, M.-F., FEBS Lett., 406 (1997) 284.

    Google Scholar 

  9. 9.

    Lebrun, B., Romi-Lebrun, R., Martin-Eauclaire, M.-F., Yasuda, A., Ishiguro, M., Oyama, Y., Pongs, O. and Nakajima, T., Biochem. J., 328 (1997) 321.

    Google Scholar 

  10. 10.

    Crest, M., Jacquet, G., Gola, M., Zerrouk, H., Benslimane, A., Rochat, H., Mansuelle, P. and Martin-Eauclaire, M.F., J. Biol. Chem., 267 (1992) 1640.

    Google Scholar 

  11. 11.

    Laraba-Djebari, F., Legros, C., Crest, M., Céard, B., Romi, R., Mansuelle, P., Jacquet, G., Van Rietschoten, J., Gola, M., Rochat, H., Bougis, P. E. and Martin-Eauclaire, M.-F., J. Biol. Chem., 269 (1994) 32835.

    Google Scholar 

  12. 12.

    Romi-Lebrun, R., Lebrun, B., Martin-Eauclaire, M.-F., Ishiguro, M., Escoubas, P., Wu, F.Q., Hisada, M., Pongs, O. and Nakajima, T., Biochemistry, 36 (1997) 13473.

    Google Scholar 

  13. 13.

    Garcia, M.L., Garcia-Calvo, M., Hidalgo, P., Lee, A. and McKinnon, R., Biochemistry, 33 (1994) 6834.

    Google Scholar 

  14. 14.

    Rogowski, R.S., Krueger, B.K., Collins, J.H. and Blaustein, M.P., Proc. Natl. Acad. Sci. USA, 91 (1994) 1475.

    Google Scholar 

  15. 15.

    Garcia-Calvo, M., Leonard, R.J., Novick, J., Stevens, S.P., Schmalhofer, W., Kaczorowski, G.J. and Garcia, M.L., J. Biol. Chem., 267 (1993) 1640.

    Google Scholar 

  16. 16.

    Possani, L.D., Martin, B.M. and Svendsen, I.B., Carlsberg Res. Commun., 47 (1982) 285.

    Google Scholar 

  17. 17.

    Nieto, A.R., Gurrola, G.B., Vaca, L. and Possani, L.D., Toxicon., 34 (1996) 913.

    Google Scholar 

  18. 18.

    Rogowski, R.S., Collins, J.H., O'Neill, T.J., Gustafson, T.A., Werkman, T.R., Rogowski, M.A., Tenenholz, T.C., Weber, D.J. and Blaustein, M.P., Mol. Pharmacol., 50 (1996) 1167.

    Google Scholar 

  19. 19.

    Martin, B.M., Ramirez, A.N., Gurrola, G.B., Nobile, M., Prestipino, G. and Possani, L., Biochem. J., 304 (1994) 51.

    Google Scholar 

  20. 20.

    Galvez, A., Gimenez-Gallelgo, G., Reuben, J.P., Roy-Contancin, L., Feigenbaum, P., Kaczorowski, G.J. and Garcia, M.L., J. Biol. Chem., 265 (1990) 11083.

    Google Scholar 

  21. 21.

    Gimenez-Gallego, G., Naira, M.A., Reuben, J.P., Kate, G.M., Kaczorowski, G.J. and Garcia, M.L., Proc. Natl. Acad. Sci. USA, 85 (1988) 3329.

    Google Scholar 

  22. 22.

    Lucchesi, K., Ravindran, A., Young, H. and Moczydlowski, E., J. Membr. Biol., 109 (1989) 269.

    Google Scholar 

  23. 23.

    Harvey, A.L., Vantapour, E.G., Rowan, E.G., Pinkasfeld, S., Vita, C., Menez, A. and Martin-Eauclaire, M.-F., Toxicon., 33 (1995) 425.

    Google Scholar 

  24. 24.

    Grishin, E.V., Yu, V., Korolkova, S.A., Lipkin, A.V., Nosyreva, E.D., Pluzhnikov, K.A., Sukhanov, S.V and Volkova, T.M., Pure Appl. Chem., 68 (1996) 2105.

    Google Scholar 

  25. 25.

    Goldstein, S.A.N., Pheasant, D.J. and Miller, C., Neuron, 12 (1994) 1377.

    Google Scholar 

  26. 26.

    Miller, C., Neurone, 15 (1995) 5.

    Google Scholar 

  27. 27.

    Aiyar, J., Withka, J.M., Rizzi, J.P., Singleton, D.H., Andrews, G.C., Simon, M., Dethlefs, B., Lee, C.-L., Hall, J.E., Gutman, G.A. and Chandy, K.G., Neuron, 15 (1995) 1169.

    Google Scholar 

  28. 28.

    Fontecilla-Camps, J.C., Almassy, R.J., Ealick, S.E., Suddath, F.L., Watt, D.D., Feldman, R.J. and Bugg, C.E., Proc. Natl. Acad. Sci. USA, 77 (1980) 6496.

    Google Scholar 

  29. 29.

    Ovchinnikov, Y.A., Pure Appl. Chem., 56 (1984) 1049.

    Google Scholar 

  30. 30.

    Fontecilla-Camps, J.C., Habersetzer-Rochat, C. and Rochat, H., Proc. Natl. Acad. Sci. USA, 85 (1988) 7443.

    Google Scholar 

  31. 31.

    Bontems, F., Roumestand, C., Boyot, P., Gilquin, B., Doljansky, Y., Menez, A. and Toma, F., Eur. J. Biochem., 196 (1991) 19.

    Google Scholar 

  32. 32.

    Sabatier, J.M., Zerrouk, H., Darbon, H., Mabrouk, K., Benslimane, A., Rochat, H., Martin-Eauclaire, M.-F. and Van Rietschoten, J., Biochemistry, 32 (1993) 2763.

    Google Scholar 

  33. 33.

    Romi, R., Crest, M., Gola, M., Sampieri, F., Jacquet, G., Zerrouk, H., Mansuelle, P., Sorokine, O., Van Dersaller, A., Rochat, H., Martin-Eauclaire, M.-F. and Van Rietschoten, J., J. Biol. Chem., 268 (1993) 26302.

    Google Scholar 

  34. 34.

    Fernandez, I., Romi, R., Szendeffy, S., Martin-Eauclaire, M.-F., Rochat, H., Pons, M. and Giralt, E., Biochemistry, 33 (1994) 14256.

    Google Scholar 

  35. 35.

    Gairi, M., Romi, R., Fernandez, I., Rochat, H., Martin-Eauclaire, M.-F., Van Rietschoten, J., Pons, M. and Giralt, E., J. Pept. Sci., 3 (1997) 1.

    Google Scholar 

  36. 36.

    Bougis, P.E., Rochat, H. and Smith, L., J. Biol. Chem., 264 (1989) 19259.

    Google Scholar 

  37. 37.

    Zilberberg, N., Gordon, D., Pelhate, M., Adams, M.E., Norris, T.N., Zlotkin, E. and Gurevitz, M., Biochemistry, 35 (1996) 10215.

    Google Scholar 

  38. 38.

    Bouhaouada-Zahar, B., Ducancel, F., Zenouaki, I., Ben Khalifa, R., Borchani, L., Pelhate, M., Boulain, J.-C., El Ayeb, M., Menez, A. and Karaoui, H., Eur. J. Biochem., 238 (1996) 653.

    Google Scholar 

  39. 39.

    Dimarq, J.L., Hoffmann, D., Meister, M., Bulet, P., Lanot, R., Reichhart, J.-M. and Hoffmann, J.A., Eur. J. Biochem., 221 (1994) 201.

    Google Scholar 

  40. 40.

    Gurevitz, M. and Zilberberg, N., J. Toxicol. Toxin Rev., 13 (1994) 65.

    Google Scholar 

  41. 41.

    Izard, J.W. and Kendall, D.A., Mol. Microbiol., 13 (1994) 765.

    Google Scholar 

  42. 42.

    Dalbey, R.E. and Von Heijne, G., Trends Biochem. Sci., 17 (1992) 474.

    Google Scholar 

  43. 43.

    Becerril, B., Corona, M., Garcia, M., Bolivar, F. and Possani, L.D., J. Toxicol. Toxin Rev., 14 (1995) 339.

    Google Scholar 

  44. 44.

    Eipper, B.A., Stoffers, D.A. and Mains, R.E., Annu. Rev. Neurosci., 15 (1992) 57.

    Google Scholar 

  45. 45.

    Delabre, M.-L., Pasero, P., Marilley, M. and Bougis, P.E., Biochemistry, 34 (1995) 6729.

    Google Scholar 

  46. 46.

    Becerril, B., Corona, M., Mejia, M.C., Martin, B.M., Lucas, S., Bolivar, F. and Possani, L.D., FEBS Lett., 335 (1993) 6.

    Google Scholar 

  47. 47.

    Corona, M., Zurita, M., Possani, L.D. and Becerril, B., Toxicon., 34 (1996) 251.

    Google Scholar 

  48. 48.

    Legros, C., Bougis, P.E. and Martin-Eauclaire, M.-F., FEBS Lett., 402 (1997) 45.

    Google Scholar 

  49. 49.

    Park, C.S., Hausdorff, S.F. and Miller, C., Neuron, 9 (1991) 307.

    Google Scholar 

  50. 50.

    Park, C.S. and Miller, C., Biochemistry, 31 (1992) 7749.

    Google Scholar 

  51. 51.

    Legros, C., Feyfant, E., Sampieri, F., Rochat, H., Bougis, P.E. and Martin-Eauclaire, M.-F., FEBS Lett., 417 (1997) 123.

    Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Marie-France Martin-Eauclaire.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Legros, C., Bougis, P.E. & Martin-Eauclaire, MF. Molecular biology of scorpion toxins active on potassium channels. Perspectives in Drug Discovery and Design 15, 1–14 (1999).

Download citation

  • gene
  • potassium channel
  • scorpion
  • toxin