Differential mechanism of action of the pyrethroid tetramethrin on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels.
Rat dorsal root ganglion neurons are endowed with tetrodotoxin-sensitive(TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels. The pyrethroid insecticides, which are known to keep sodium channels open for a prolonged period of time, cause differential effects on the two types of sodium channels. The whole-cell patch clamp experiments were performed with rat dorsal root ganglion neurons in primary culture. In TTX-S sodium channels, the slow sodium current during step depolarization was increased somewhat by tetramethrin, and a tail sodium current with a slowly rising and falling phase appeared upon repolarization. The tail current developed even after the sodium current during depolarization had subsided. In TTX-R sodium channels, the slow sodium current during step depolarization was increased markedly by tetramethrin, and upon repolarization a large instantaneous tail current was generated and decayed slowly. The steady-state sodium channel inactivation curve was shifted by tetramethrin in the hyperpolarizing direction in both TTX-S and TTX-R channels. The sodium conductance-voltage curve also was shifted by tetramethrin in the hyperpolarizing direction in both TTX-S and TTX-R channels, and the latter was affected more strongly than the former. At a concentration of 10 microM, the highest concentration tested, tetramethrin modified only 12% of the TTX-S sodium channels, whereas the modification was as high as 81% in the TTX-R. Even at 10 nM, 1.3% of TTX-R sodium channels were modified; this accounts for the high potency of tetramethrin as an insecticide.(ABSTRACT TRUNCATED AT 250 WORDS)
Tatebayashi
H
H
Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois.
Narahashi
T
T
D000818:Animals; D004351:Drug Resistance; D066298:In Vitro Techniques; D007306:Insecticides / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D011722:Pyrethrins / Q000494:pharmacology*; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology*
D007306:Insecticides; D011722:Pyrethrins; D015222:Sodium Channels; D013779:Tetrodotoxin; C009424:tetramethrin