Mechanisms of action and resistance of sodium channel-targeted insecticides

钠通道靶向杀虫剂的作用机制和耐药性

• 批准号: 7575631
• 负责人: KE DONG
• 金额: $ 28.33万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575631
• 关键词: Address; Affect; Allergens; Amino Acids; Arthropods; Binding; Binding Sites; Chemicals; Culicidae; Development; Dictyoptera; Drug Metabolic Detoxication; Future; Gene Mutation; Genes; Goals; Grant; Health; Human; Insect Control; Insecta; Insecticide Resistance; Insecticides; Knowledge; Metabolic; Molecular; Molecular Analysis; Molecular Genetics; Monitor; Musca domestica; Mutation; Neurons; Population; Property; Relative (related person); Research; Research Personnel; Resistance; Series; Site; Site-Directed Mutagenesis; Sodium Channel; Source; Staging; Ticks; Toxic effect; base; indoxacarb; insect allergen; pathogen; programs; pyrethroid; receptor; resistance mechanism; resistance mutation; tool; voltage

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand the molecular basis of insecticide resistance in arthropod pests. As carriers of numerous human pathogens and/or a major source of indoor allergens, arthropod pests, such as cockroaches, mosquitoes and ticks, are major threats to human health. Strategies for the control of these arthropod pests rely heavily on the use of insecticides, such as pyrethroids which act on voltage-gated sodium channels. However, the intensive use of pyrethroids has led to rapid development of insecticide resistance worldwide. One major mechanism of resistance, knockdown resistance (kdr), reduces neuronal sensitivity and confers cross-resistance to all pyrethroid insecticides. Research in the past decade shows that mutations in the sodium channel gene are responsible for kdr in various arthropod pest species. Our recent findings indicate that there are two distinct mechanisms of pyrethroid resistance: one via reducing pyrethoid-binding and the other via altering gating properties. These results set a critical stage for hypothesis-driven research to elucidate the pyrethroid-binding site and how alterations of gating properties of sodium channels cause pyrethroid resistance. We have also begun to study the molecular action of a newly developed insecticide, indoxacarb, that acts on the sodium channel by a mechanism completely different from that of pyrethroids. The central hypothesis to be examined in this proposal is that these two classes of insecticides bind to distinct receptor sites on the sodium channel and trap distinct voltage-sensing domains in the outward configuration, modifying sodium channel function. Pyrethroids interact mainly with domain II of sodium channels, inhibiting channel deactivation, whereas indoxacarb interacts mainly with domain IV, promoting channel inactivation. The three specific aims of this proposal are: 1. Comprehensive analysis of the molecular determinants of pyrethroid-binding based on naturally occurring kdr mutations and site-directed mutagenesis. 2. Determine the molecular basis of pyrethroid resistance caused by alterations in sodium channel gating properties. 3. Characterize the molecular action of indoxacarb on the insect sodium channel.

描述（由申请人提供）：本研究的长期目标是了解节肢动物害虫抗药性的分子基础。作为多种人类病原体的携带者和/或室内过敏原的主要来源，节肢动物害虫，例如蟑螂、蚊子和蜱虫，是对人类健康的主要威胁。控制这些节肢动物害虫的策略在很大程度上依赖于杀虫剂的使用，例如作用于电压门控钠通道的拟除虫菊酯。然而，拟除虫菊酯的大量使用导致了全球范围内杀虫剂抗药性的迅速发展。抗性的一种主要机制是击倒抗性 (kdr)，它会降低神经元敏感性并赋予对所有拟除虫菊酯杀虫剂的交叉抗性。过去十年的研究表明，钠通道基因的突变导致了多种节肢动物害虫的 kdr。我们最近的研究结果表明，拟除虫菊酯抗性有两种不同的机制：一种是通过减少拟除虫菊酯结合，另一种是通过改变门控特性。这些结果为假设驱动的研究奠定了关键阶段，以阐明拟除虫菊酯结合位点以及钠通道门控特性的改变如何导致拟除虫菊酯耐药性。我们还开始研究新开发的杀虫剂茚虫威的分子作用，它通过与拟除虫菊酯完全不同的机制作用于钠通道。该提案要检验的中心假设是，这两类杀虫剂与钠通道上不同的受体位点结合，并在向外配置中捕获不同的电压感应域，从而改变钠通道功能。拟除虫菊酯主要与钠通道的结构域 II 相互作用，抑制通道失活，而茚虫威主要与结构域 IV 相互作用，促进通道失活。该提案的三个具体目标是： 1. 基于自然发生的 kdr 突变和定点诱变，全面分析拟除虫菊酯结合的分子决定因素。 2. 确定由钠通道门控特性改变引起的拟除虫菊酯抗性的分子基础。 3. 表征茚虫威对昆虫钠通道的分子作用。