State-dependent block of rat Nav1.4 sodium channels expressed in xenopus oocytes by pyrazoline-type insecticides.
Insecticidal pyrazolines inhibit voltage-sensitive sodium channels of both insect and mammalian neurons in a voltage-dependent manner. Studies on the effects of pyrazoline insecticides on mammalian sodium channels have been limited to experimentation on the tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium channel populations of rat dorsal root ganglion (DRG) neurons. In this study, we examined the effects of the insecticidal pyrazolines indoxacarb, the N-decarbomethoxyllated metabolite of indoxacarb (DCJW), and RH 3421 on rat Na(v)1.4 sodium channels expressed in Xenopus laevis oocytes using the two-electrode voltage clamp technique. Both DCJW and RH 3421 were ineffective inhibitors of rat Na(v)1.4 sodium channels at a membrane potential of -120 mV, but depolarization to -60 mV or -30 mV during insecticide exposure resulted in substantial block. Inhibition by pyrazoline insecticides was nearly irreversible with washout, but repolarization of the membrane relieved block. DCJW and RH 3421 also caused hyperpolarizing shifts in the voltage dependence of slow inactivation without affecting the voltage dependence of activation or fast inactivation. These results suggest that DCJW and RH 3421 interact specifically with the slow inactivated state of the sodium channel. Indoxacarb did not cause block at any potential, yet it interfered with the ability of DCJW, but not RH 3421, to inhibit sodium current. Phenytoin, an anticonvulsant, reduced the efficacy of both DCJW and RH 3421. These data imply that the binding site for pyrazoline insecticides overlaps with that for therapeutic sodium channel blockers.
Silver
Kristopher
K
Department of Entomology, New York State Agricultural Experiment Station, Cornell University, Geneva, NY 14456, USA.
Soderlund
David M
DM
D000818:Animals; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004347:Drug Interactions; D004594:Electrophysiology; D007306:Insecticides / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010078:Oxazines / Q000633:toxicity; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000633:toxicity; D010957:Plasmids / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D014981:Xenopus
D018076:DNA, Complementary; D007306:Insecticides; D009124:Muscle Proteins; D010078:Oxazines; D010671:Phenylurea Compounds; D011720:Pyrazoles; C466180:Scn4a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C401104:indoxacarb; C072441:RH 3421