Sodium channels and GABAA receptor-channel complex as targets of environmental toxicants

Toshio Narahashi, Donald B. Carter, Joseph Frey, Kenneth S Ginsburg, Beverly J. hamilton, Keiichi Nagata, Mary Louise Roy, Jin ho Song, Hideharu Tatebayashi

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Voltage-activated sodium channels and GABAA receptor-chloride channel complex are among the most important target sites of various environmental neurotoxicants. Pyrethroids keep the sodium channels open for prolonged periods of time leading to hyperexcitation of the entire nervous system. In rat cerebellar Purkinje neurons and dorsal root ganglion neurons, only about 1% of sodium channel population needed to be modified by the pyrethroid tetramethrin to increase the depolarizing after-potential to the level of the threshold membrane potential for generation of repetitive after-discharges. This concept of toxicity amplification is applicable to other chemicals that go through a threshold phenomenon to exert their effects. The potency of pyrethroids on neuronal sodium channels increased with lowering the temperature with a Q10 value of 0.2. The selective pyrethroid toxicity between mammals and insects can be quantitatively explained on the basis of the differences in 5 factors, i.e. the intrinsic sodium channel sensitivity, the sodium channel modification due to temperature difference, the reversibility of sodium channel, the detoxication of pyrethroids, and body size. These 5 factors are multiplied to approximately 2000 which is in the same order of magnitude as that of the difference in LD50. Dieldrin had a dual action on the GABAA receptor-chloride channel complex of rat dorsal root ganglion neurons. The initial transient potentiation of GABA-induced currents after application of dieldrin was followed by a suppression. Dieldrininduced potentiation of current was observed only when the γy2 subunit was present in embryonic kidney cells (HEK-293) transfected with GABA receptor subunits. Dieldrin-induced suppression was observed in the presence and absence of the γ2 subunit. The dieldrin suppression of GABA-induced currents is deemed directly responsible for hyperactive symptoms of poisoning in animals.

Original languageEnglish (US)
Pages (from-to)239-245
Number of pages7
JournalToxicology Letters
Volume82-83
Issue numberC
DOIs
StatePublished - 1995
Externally publishedYes

Keywords

  • Dieldrin
  • GABA receptor
  • GABA receptor subunits
  • Pyrethroids
  • Selective toxicity
  • Sodium channels

ASJC Scopus subject areas

  • Toxicology

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    Narahashi, T., Carter, D. B., Frey, J., Ginsburg, K. S., hamilton, B. J., Nagata, K., Roy, M. L., Song, J. H., & Tatebayashi, H. (1995). Sodium channels and GABAA receptor-channel complex as targets of environmental toxicants. Toxicology Letters, 82-83(C), 239-245. https://doi.org/10.1016/0378-4274(95)03482-X