Protein Information

ID 40
Name sodium channel (protein family or complex)
Synonyms Sodium channel

Compound Information

ID 1582
Name indoxacarb
CAS

Reference

PubMed Abstract RScore(About this table)
16325912 Song W, Liu Z, Dong K: Molecular basis of differential sensitivity of insect sodium channels to DCJW, a bioactive metabolite of the oxadiazine insecticide indoxacarb. Neurotoxicology. 2006 Mar;27(2):237-44. Epub 2005 Dec 2.
Indoxacarb (DPX-JW062) was recently developed as a new oxadiazine insecticide with high insecticidal activity and low mammalian toxicity. Previous studies showed that indoxacarb and its bioactive metabolite, N-decarbomethoxyllated JW062 (DCJW), block insect sodium channels in nerve preparations and isolated neurons. However, the molecular mechanism of indoxacarb/DCJW action on insect sodium channels is not well understood. In this study, we identified two cockroach sodium channel variants, BgNa (v) 1-1 and BgNa (v) 1-4, which differ in voltage dependence of fast and slow inactivation, and channel sensitivity to DCJW. The voltage dependence of fast inactivation and slow inactivation of BgNa (v) 1-4 were shifted in the hyperpolarizing direction compared with those of BgNa (v) 1-1 channels. At the holding potential of -90 mV, 20 microM of DCJW reduced the peak current of BgNa (v) 1-4 by about 40%, but had no effect on BgNa (v) 1-1. However, at the holding potential of -60 mV, DCJW also reduced the peak currents of BgNa (v) 1-1 by about 50%. Furthermore, DCJW delayed the recovery from slow inactivation of both variants. Substitution of E1689 in segment 4 of domain four (IVS4) of BgNa (v) 1-4 with a K, which is present in BgNa (v) 1-1, was sufficient to shift the voltage dependence of fast and slow inactivation of BgNa (v) 1-4 channels to the more depolarizing membrane potential close to that of BgNa (v) 1-1 channels. The E1689K change also eliminated the DCJW inhibition of BgNa (v) 1-4 at the hyperpolarizing holding potentials. These results show that the E1689K change is responsible for the difference in channel gating and sensitivity to DCJW between BgNa (v) 1-4 and BgNa (v) 1-1. Our results support the notion that DCJW preferably acts on the inactivated state of the sodium channel and demonstrate that K1689E is a major molecular determinant of the voltage-dependent inactivation and state-dependent action of DCJW.
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