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-sensiti ve(TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channels. The pyre throid insecticides, which are known to keep sodium channels open for a prolonged period of time, cause differential effects on the two type s of sodium channels. The whole-cell patch clamp experiments were perf ormed 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 wit h a slowly rising and falling phase appeared upon repolarization. The tail current developed even after the sodium current during depolariza tion had subsided. In TTX-R sodium channels, the slow sodium current d uring step depolarization was increased markedly by tetramethrin, and upon repolarization a large instantaneous tail current was generated a nd decayed slowly. The steady-state sodium channel inactivation curve was shifted by tetramethrin in the hyperpolarizing direction in both T TX-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 t he former. At a concentration of 10 mu M, the highest concentration te sted, tetramethrin modified only 12% of the TTX-S sodium channels, whe reas 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 hig h potency of tetramethrin as an insecticide. In conclusion, although b oth TTX-S and TTX-R sodium channels are modified by tetramethrin, the detailed kinetic mechanisms are different and TTX-R channels are much more sensitive to tetramethrin.