Nerve Membrane Ionic Channels as the Target of Toxicants

  • T. Narahashi
Part of the Archives of Toxicology book series (TOXICOLOGY, volume 9)


Certain natural toxins and environmental agents have been found to act on nerve membrane ionic channels in a highly specific manner. For example, the puffer fish poison, tetrodotoxin, blocks the sodium channel without affecting its gating mechanism. The sodium channel is also the major target site of the pyrethroid and DDT insecticides. Patch clamp single channel recording experiments with cultured neuroblastoma cells have revealed that individual sodium channels are kept open much longer in the presence of the pyrethroid tetramethrin than in control. This effect accounts for a marked prolongation of sodium current by tetramethrin observed in giant axons. The prolonged sodium current increases the depolarizing after-potential which in turn generates repetitive after-discharges. The symptoms of pyrethroid poisoning in animals can be explained on this basis. Only a very small fraction of sodium channels, less than 1%, needs to be modified by pyrethroids to produce the symptoms of poisoning. Fenvalerate, a cyano-containing type II pyrethroid, prolongs the sodium channel open time much more drastically than tetramethrin. This causes a persistent depolarization of the membrane, which in turn blocks conduction.

Key words

Pyrethroids Sodium channels Ionic channels Sodium current Tetrodotoxin Single channel recording 


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  1. Armstrong CM (1975) Ionic pores, gates, and gating currents. Quart Rev Biophys 7: 179–210CrossRefGoogle Scholar
  2. Baker PF, Hodgkin AL, Shaw TI (1961) Replacement of the protoplasm of a giant nerve fibre with artificial solutions. Nature 190: 885–887PubMedCrossRefGoogle Scholar
  3. Catterall WA (1980) Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes. Ann Rev Pharmacol Toxicol 20: 15–43CrossRefGoogle Scholar
  4. Cuervo LA, Adelman WJ, Jr (1970) Equilibrium and kinetic properties of the interaction between te- trodotoxin and the excitable membrane of the squid giant axon. J Gen Physiol 55: 309–335PubMedCrossRefGoogle Scholar
  5. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391: 85–100PubMedCrossRefGoogle Scholar
  6. Hille B (1975) The receptor for tetrodotoxin and saxitoxin. A structural hypothesis. Biophys J 15: 615–619PubMedCrossRefGoogle Scholar
  7. Hodgkin AL, Huxley AF, Katz B (1952) Measurements of current-voltage relations in the membrane of the giant axon of Loligo. J Physiol 116: 424–448PubMedGoogle Scholar
  8. Holloway SF, Salgado VL, Wu CH, Narahashi T (1984) Maintained opening of single Na channels by fenvalerate. 14th Ann Mtg Soc Neurosci Abstr Vol 10, p 864Google Scholar
  9. Kao CY, Nishiyama A (1965) Actions of saxitoxin in peripheral neuromuscular systems. J Physiol 180: 50–66PubMedGoogle Scholar
  10. Lund AE, Narahashi T (1981a) Modification of sodium channel kinetics by the insecticide tetramethrin in crayfish giant axons. Neurotoxicology 2:213–229Google Scholar
  11. Lund AE, Narahashi T (1981b) Kinetics of sodium channel modification by the insecticide tetramethrin in squid axon membranes. J Pharmacol Exp Ther 219:464–473Google Scholar
  12. Lund AE, Narahashi T (1982) Dose-dependent interaction of the pyrethroid isomers with sodium channels of squid axon membranes. Neurotoxicology 3: 11–24PubMedGoogle Scholar
  13. Lund AE, Narahashi T (1983) Kinetics of sodium channel modification as the basis for the variation in the nerve membrane effects of pyrethroids and DDT analogs. Pesticide Biochem Physiol 20: 203–216CrossRefGoogle Scholar
  14. Moore JW, Narahashi T, Shaw TI (1967) An upper limit to the number of sodium channels in nerve membrane? J Physiol 188: 99–105PubMedGoogle Scholar
  15. Narahashi T (1971) Effects of insecticides on excitable tissues. In: Beament JWL, Treherne JE, Wigglesworth VB (eds) Advances in Insect Physiology, Vol 8, Academic Press, New York, pp 1–93Google Scholar
  16. Narahashi T (1972) Mechanism of action of tetrodotoxin and saxitoxin on excitable membranes. Fed Proc 31: 1124–1132PubMedGoogle Scholar
  17. Narahashi T (1974) Chemicals as tools in the study of excitable membranes. Physiol Rev 54: 813–889PubMedCrossRefGoogle Scholar
  18. Narahashi T (1976) Effects of insecticides on nervous conduction and synaptic transmission. In: Wilkinson CF (ed) Insecticide Biochemistry and Physiology, Plenum Publ Corp, New York, pp 327–352Google Scholar
  19. Narahashi T (1981a) Mode of action of chlorinated hydrocarbon pesticides on the nervous system. In: Khan MAQ (ed) Halogenated Hydrocarcons: Health and Ecological Effects, Pergamon Press, Elmsford, NY, pp 222–242Google Scholar
  20. Narahashi T (1981b) Modulation of nerve membrane sodium channels by chemicals. J Physiol, Paris 77:1093–1101Google Scholar
  21. Narahashi T (1982) Cellular and molecular mechanisms of action of insecticides: Neurophysiological approach. Neurobehavioral Toxicol Teratol 4: 753–758Google Scholar
  22. Narahashi T (1983) Neurophysiological study of pyrethroids: Molecular and membrane mechanism of action. In: Miyamoto J, Kearney PC (eds) Pesticide Chemistry: Human Welfare and the Environment, Vol 2, Natural Products, Pergamon Press, Oxford, p 179–186Google Scholar
  23. Narahashi T (1984a) Pharmacology of nerve membrane sodium channels. In: Baker PF (ed) Current Topics in Membranes and Transport, Vol 22, The Squid Axon, Academic Press, New York, pp 483–516Google Scholar
  24. Narahashi T (1984b) Nerve membrane sodium channels as the target of pyrethroids. In: Narahashi T (ed) Cellular and Molecular Neurotoxicology, Raven Press, New York, p 85–108Google Scholar
  25. Narahashi T (1984c) Drug-ionic channel interactions: Single-channel measurements. Ann Neurol 16: S39 - S51PubMedCrossRefGoogle Scholar
  26. Narahashi T (1985) Nerve membrane ionic channels as the primary target of pyrethroids. Neuro-toxicology 6: 3–22Google Scholar
  27. Narahashi T, Anderson NC (1967) Mechanism of excitation block by the insecticide allethrin applied externally and internally to squid giant axons. Toxicol Appl Pharmacol 10: 529–547PubMedCrossRefGoogle Scholar
  28. Narahashi T, Haas HG (1967) DDT: Interaction with nerve membrane conductance changes. Science 157: 1438–1440PubMedCrossRefGoogle Scholar
  29. Narahashi T, Haas HG (1968) Interaction of DDT with the components of lobster nerve membrane conductance. J Gen Physiol 51: 177–198PubMedCrossRefGoogle Scholar
  30. Narahashi T, Lund AE (1980) Giant axons as models for the study of the mechanism of action of insecticides. In: Insect Neurobiology and Pesticide Action (Neurotox 79). Soc Chem Industry, London, p 497–505Google Scholar
  31. Narahashi T, Anderson NC, Moore JW (1967) Comparison of tetrodotoxin and procaine in internally perfused squid giant axons. J Gen Physiol 50: 1413–1428PubMedCrossRefGoogle Scholar
  32. Narahashi T, Moore JW, Scott WR (1964) Tetrodotoxin blockage of sodium conductance increase in lobster giant axons. J Gen Physiol 47: 965–974PubMedCrossRefGoogle Scholar
  33. Narahashi T, Deguchi T, Urakawa N, Ohkubo Y (1960) Stabilization and rectification of muscle fiber membrane by tetrodotoxin. Amer J Physiol 198: 934–938PubMedGoogle Scholar
  34. Neher E, Sakmann B (1976) Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature 260: 779–802CrossRefGoogle Scholar
  35. Quandt FN, Yeh JZ, Narahashi T (1985) All or none block of single Na+ channels by tetrodotoxin. Neurosci Letters 54: 77–83CrossRefGoogle Scholar
  36. Ritchie JM (1979) A pharmacological approach to the structure of sodium channels in myelinated axons. Ann Rev Neurosci 2: 341–362PubMedCrossRefGoogle Scholar
  37. Shanes AM, Freygang WH, Grundfest H, Amatniek E (1959) Anesthetic and calcium action in the voltage clamped squid giant axon. J Gen Physiol 42: 793–802PubMedCrossRefGoogle Scholar
  38. Tanguy J, Yeh JZ, Narahashi T (1984) Interaction of batrachotoxin with sodium channels in squid axons. Biophys J 45: 184aGoogle Scholar
  39. Taylor RE (1959) Effect of procaine on electrical properties of squid axon membranes. Amer J Physiol 196: 1071–1078PubMedGoogle Scholar
  40. Wouters W, van den Bercken J (1978) Action of pyrethroids. Gen Pharmacol 9: 387–398PubMedCrossRefGoogle Scholar
  41. Yamamoto D, Quandt FN, Narahashi T (1983) Modification of single sodium channels by the insecticide tetramethrin. Brain Res 274: 344–349PubMedCrossRefGoogle Scholar
  42. Yamamoto D, Yeh JZ, Narahashi T (1986) Ion permeation and selectivity of squid axon sodium channels modified by tetramethrin. Brain Res 372: 193–197PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • T. Narahashi
    • 1
  1. 1.Department of PharmacologyNorthwestern University Medical SchoolChicagoUSA

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