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）：这项研究的长期目标是了解节肢动物害虫中杀虫剂抗性的分子基础。作为众多人类病原体和/或室内过敏原的主要来源，节肢动物害虫（例如蟑螂，蚊子和壁虱）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取决于杀虫剂的使用，例如对电压门控钠通道作用的拟甲虫素。但是，大量使用拟除虫菊酯导致了全球杀虫剂耐药性的迅速发展。一种主要的抗性，抗抑制性（KDR）的机制，降低了神经元的敏感性，并赋予对所有拟除虫菊酯杀虫剂的交叉抗性。在过去的十年中，研究表明，钠通道基因中的突变是各种节肢动物害虫物种中KDR的原因。我们最近的发现表明，拟除虫菊酯耐药性有两种不同的机制：一种是通过减少拟拟南芥结合，另一个是通过改变门控性能的。这些结果为假设驱动的研究树立了关键阶段，以阐明拟除虫菊酯结合位点以及钠通道的门控性能的变化如何引起拟除虫菊酯抗性。我们还开始研究新开发的杀虫剂IndoxaCarb的分子作用，该杀虫剂通过与拟除虫菊酯完全不同的机制在钠通道上作用。该提案中要研究的中心假设是，这两类杀虫剂与钠通道上的不同受体位点结合，并在外部配置中捕获不同的电压感应域，从而改变了钠通道功能。拟甲状腺主要与钠通道的结构域II相互作用，抑制通道失活，而Indoxacarb主要与域IV相互作用，从而促进通道失活。该提案的三个特定目的是：1。基于天然存在的KDR突变和位置定向诱变的拟除虫菊酯结合的分子决定因素的全面分析。 2。确定由钠通道门控性能改变引起的拟除虫菊酯耐药性的分子基础。 3。表征吲哚可龙在昆虫钠通道上的分子作用。