Time course and temperature dependence of allethrin modulation of sodium channels in rat dorsal root ganglion cells.
Key effects of the pyrethroid insecticide allethrin, delivered to or washed out from cells at 10 or 100 microM in 0.1% DMSO, on neuronal Na(+) channel currents were studied in rat dorsal root ganglion (DRG) cells under whole-cell patch clamp. Tetrodotoxin-resistant (TTX-R) Na(+) channels were more responsive to allethrin than tetrodotoxin-sensitive (TTX-S) Na(+) channels. On application of 10 or 100 microM allethrin to cells with TTX-R Na(+) channels, the Na(+) tail current during repolarization developed a large slowly decaying component within 10 min. This slow tail developed multiphasically, suggesting that allethrin gains access to Na(+) channels by a multiorder process. On washout (with 0.1% DMSO present), the slow tail current disappeared monophasically (exponential tau=188+/-44 s). Development and washout rates did not depend systematically on temperature (12 degrees, 18 degrees, or 27 degrees C), but washout was slowed severely if DMSO was absent. As the duration of a depolarizing pulse was increased (range 0.32-10 ms), the amplitude of the slow component of the succeeding tail conductance first increased then decreased. Tail current amplitude had the same dependence on preceding pulse duration (at 18 degrees ) at 10 or 100 microM, consistent with allethrin modification of Na(+) channels at rest before opening. At 10 microM, slow tail conductance was at maximum 40% of the peak conductance during the previous depolarization, independent of temperature; evidently, the fraction of open modified channels did not change. However, at low temperature, the tail is more prolonged, bringing more Na(+) ions into a cell. In functioning neurons, this Na(+) influx would cause a larger depolarizing afterpotential, a condition favoring the repetitive discharges, which are signatory of pyrethroid intoxication.
Ginsburg
K
K
Department of Molecular Pharmacology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL, USA. kginsbu@luc.edu
Narahashi
T
T
D000487:Allethrins / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000502:physiology*; D007306:Insecticides / Q000494:pharmacology; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009479:Neuropeptides / Q000187:drug effects* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology*; D013696:Temperature; D013997:Time Factors
D000487:Allethrins; D007306:Insecticides; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C503480:Scn9a protein, rat; D015222:Sodium Channels