INSECTICIDE ACTIONS ON GABA-A RECEPTORS

描述（由申请方提供）：3-氨基丁酸A型（GABA-A）受体是中枢神经系统中主要的抑制性神经递质门控离子通道，也是多种药物（包括杀虫剂氟虫腈）的重要靶标。杀虫剂氟虫腈是许多广泛使用的害虫控制产品中的活性成分，医学文献中已报告人类接触这些制剂，导致恶心、眩晕或癫痫发作。拟开展的工作将详细研究非泼罗尼及其代谢产物非泼罗尼砜与哺乳动物GABA-A受体（由11、22和32 L亚基组成）的相互作用。有两个目标。第一个目的是建立非泼罗尼和非泼罗尼砜对哺乳动物112232 L GABA-A受体的动力学作用机制。第二个目的是确定M2和M3跨膜结构域突变对非泼罗尼作用的耐药性机制。这项工作的结果将有助于更好地确定杀虫剂毒性的机制，并可能有助于了解如何提供保护，免受这种广泛使用的杀虫剂的神经影响。

DESCRIPTION (provided by applicant): The 3-aminobutyric acid type-A (GABA-A) receptor is the major inhibitory neurotransmitter-gated ion channel in the central nervous system, and an important target for multiple classes of pharmacological agents including the insecticide fipronil. The insecticide fipronil is the active ingredient in many widely used pest control products, and human exposure to these agents, resulting in nausea, vertigo or seizures, has been reported in the medical literature. The proposed work will examine in detail the interactions of fipronil and its metabolite fipronil sulfone with the mammalian GABA-A receptor consisting of 11, 22 and 32L subunits. There are two aims. The first aim is to establish the kinetic mechanisms of action of fipronil and fipronil sulfone on mammalian 112232L GABA-A receptor. The second aim is to determine the mechanisms of resistance to actions of fipronil conferred by mutations in the M2 and M3 transmembrane domains. The results from the work will help to better define the mechanisms of insecticide toxicity, and may be useful in learning how to provide protection from the neurological effects of this widely used insecticide.