MODE OF ACTION OF INSECTICIDES: ELECTROPHYSIOLOGICAL

杀虫剂的作用方式：电生理学

• 批准号: 3395424
• 负责人: TOSHIO NARAHASHI
• 金额: $ 25.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-05-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3395424
• 关键词: Cephalopoda; GABA receptor; Malacostraca; action potentials; axon; calcium channel; cell membrane; chemical structure function; computer simulation; dichlorodiphenyltrichloroethane; drug metabolism; electrophysiology; environmental toxicology; fresh water environment; gamma aminobutyrate; glutamate receptor; guinea pigs; insecticide biological effect; ion transport; laboratory rat; membrane potentials; microelectrodes; molecular site; neuromuscular junction; neuromuscular transmission; neuropharmacology; neurophysiology; neurotoxins; neurotransmitter receptor; oscillography; pesticide interaction; pyrethroid; saltwater environment; sodium channel; synapses; temperature; voltage /patch clamp

The long-term objectives of the proposed study are to elucidate the mechanism of action of environmentally important insecticides on the nerve membrane which is the most critical target site of various insecticides. The knowledge obtained through this research will have direct impact on our environmental concern, i.e., developments of effective therapeutic means for insecticide intoxication, and of newer insecticides which are more effective against insects yet safer for humans. The specific aims are to clarify the nature of interactions of pyrethroid and DDT-type insecticides with nerve membrane ion channels which have been demonstrated to be mainly responsible for development of the symptoms of poisoning in animals. Advanced electrophysiological techniques developed in our laboratory over many years will be fully utilized, including intracellular and extracellular microelectrode, voltage clamp, patch clamp for whole cell and single channel recording, and intracellular perfusion. These techniques will be applied to cultured neuroblastoma cells, squid and crayfish giant axons, rat and crayfish neuromuscular junctions, and hippocampus slices from guinea-pigs. Six specific projects will be investigated: 1) Modification of kinetics of sodium channels by the insecticides will be analyzed in detail; 2) pyrethroids and DDT appear to bind to a membrane site near the gating machinery as approached through the lipid phase, and this hypothesis will be demonstrated by use of various chemical agents; 3) structure-activity relationship will be determined with special reference to stereospecificity; 4) the mechanism underlying the profound negative temperature coefficient of action of the insecticides will be elucidated at the channel level; 5) the mechanism underlying the drastic effects of the pyrethroids on calcium channels will be determined; and 6) controversial results concerning the effects of pyrethroids on neuroreceptors such as GABA receptor-channel complex will be re-examined and resolved. These studies are expected to provide the basis for the molecular mechanism of action of insecticides on the nervous system.

拟议研究的长期目标是阐明 环境重要杀虫剂在神经上的作用机理 膜是各种杀虫剂的最关键目标部位。 通过这项研究获得的知识将直接影响我们 环境问题，即有效治疗手段的发展 用于杀虫剂中毒和更新的杀虫剂 对昆虫有效，但对于人类而言更安全。 具体目的是 阐明拟除虫菊酯和DDT型杀虫剂的相互作用的性质 神经膜离子通道已被证明主要是 负责发展动物中毒症状。 高级电生理技术在我们的实验室开发 多年将被充分利用，包括细胞内和 细胞外微电极，电压夹，全细胞的斑块夹， 单道通道记录和细胞内灌注。 这些技术 将应用于培养的神经母细胞瘤细胞，鱿鱼和小龙虾巨人 轴突，大鼠和小龙虾神经肌肉连接和海马切片 来自豚鼠。 将研究六个特定项目：1） 通过杀虫剂对钠通道动力学的修饰将是 详细分析； 2）拟除虫菊酯和DDT似乎与膜结合 通过脂质阶段接近门控机械附近的位置， 该假设将通过使用各种化学剂来证明。 3） 结构活性关系将通过特别参考确定 立体特定； 4）严重负面的机制 杀虫剂作用的温度系数将在 频道级别； 5） 将确定钙通道上的拟除虫菊酯； 6）有争议 关于拟除虫菊酯对神经受体的影响的结果 GABA受体通道复合物将被重新检查并解决。 这些 期望研究为分子机制提供基础 杀虫剂在神经系统上的作用。