Molecular basis of differential sensitivity of insect sodium channels to DOW, a bioactive metabolite of the oxadiazine insecticide indoxacarb
Molecular basis of differential sensitivity of insect sodium channels to DOW, a bioactive metabolite of the oxadiazine insecticide indoxacarb
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DOI：
10.1016/j.neuro.2005.10.004
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发表时间：
2006-03-01
期刊：
影响因子：
3.4
通讯作者：
Dong, K
中科院分区：
文献类型：
--
作者：
Song, WZ;Liu, ZQ;Dong, K
茚虫威（DPX-JW 062）是最近开发的一种新型恶二嗪杀虫剂，具有高杀虫活性和低哺乳动物毒性。先前的研究表明，茚虫威及其生物活性代谢产物，N-去甲氧羰基化的JW 062（DCJW），在神经制备和分离的神经元中阻断昆虫钠通道。然而，茚虫威/DCJW作用于昆虫钠通道的分子机制还不清楚。在这项研究中，我们确定了两种蟑螂钠通道变体。BgNa（v）1-1和BgNa（v）1-4，它们在快失活和慢失活的电压依赖性以及对DCJW的通道敏感性方面不同。与BgNa（v）1-1通道相比，B-Na（v）1-4通道的快失活和慢失活的电压依赖性向超极化方向移动。在-90 mV的保持电位下，20 μ M的DCJW使BgNa（v）1-4的峰电流降低约40%，但对B-Na（v）1-1没有影响。然而，在-60 rnV的保持电位下，DCJW也使BgNa（v）1-1的峰值电流降低了约50%。此外，DCJW延迟了两种变体从缓慢失活中的恢复。用BaNa（v）1-1中存在的K取代BgNa（v）1-4的结构域4（IVS 4）的片段4中的E1689足以将BgNa（v）1-4通道的快速和缓慢失活的电压依赖性转移到更接近BgNa（v）1-1通道的去极化膜电位。E1689 K的改变也消除了BgNa（v）1-4在超极化保持电位下的DCJW抑制。这些结果表明，E1689 K变化是BgNa（v）1-4和BgNa（v）1-1之间通道门控和对DCJW敏感性差异的原因。我们的研究结果支持DCJW优选作用于钠通道的失活状态的概念，并表明K1689 E是DCJW的电压依赖性失活和状态依赖性作用的主要分子决定因素。(c)2005年爱思唯尔公司All rights reserved.
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 B-Na(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 mu M of DCJW reduced the peak current of BgNa(v)1-4 by about 40%, but had no effect on B-Na(v)1-1. However, at the holding potential of -60 rnV, 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 BaNa(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 El 689K 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. (c) 2005 Elsevier Inc. All rights reserved.