Presynaptic modulation of anticholinesterase toxicity

抗胆碱酯酶毒性的突触前调节

• 批准号: 7087850
• 负责人: CAREY N POPE
• 金额: $ 31.68万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087850
• 关键词: G protein coupled receptor kinase; acetylcholinesterase; affinity chromatography; age difference; cholinergic receptors; cholinesterase inhibitors; environmental toxicology; hippocampus; laboratory rat; microdialysis; muscarinic receptor; neurotransmitter transport; organophosphorus insecticide; parathion; pesticide biological effect; phosphorylation; protein structure function; receptor binding; synapses; tissue /cell culture; toxin metabolism

DESCRIPTION (provided by applicant): The mechanism of toxicity for organophosphorus (OP) anticholinesterases involves steps which may be selectively affected by some, providing a basis for differential toxicity. Acetylcholine release and its regulation by inhibitory muscarinic autoreceptors may be pivotally important in OP toxicant-selective toxicity. Some anticholinesterases (including the oxons of both parathion and chlorpyrifos, i.e., paraoxon and chlorpyrifos oxon) directly interact with muscarinic M2 receptors, the receptor subtype of muscarinic autoreceptors. Using superfused brain slices to measure acetylcholine release, both qualitative differences in the in vitro effects of paraoxon and chlorpyrifos oxon and time-dependent differences in the alteration of muscarinic autoreceptor function following in vivo parathion and chlorpyrifos exposures were noted. It is hypothesized that muscarinic autoreceptor function is an important modifier of cholinergic toxicity and that selective modulation or age-related differences in its activity can lead to differential toxicity. In aim 1, the dose-related effects of parathion and chlorpyrifos on cholinergic toxicity and acetylcholine release in vivo using microdialysis techniques will be compared in adult rats. Aged rats appear more sensitive to the acute effects of both chlorpyrifos and parathion. Studies in aim 2 will evaluate whether acetylcholine release/autoreceptor function may contribute to aging-related differences in OP insecticide toxicity. Aim 3 will evaluate the consequences of prior modulation of autoreceptor function (by infusion of autoreceptor agonist, antagonist or M2 receptor antisense) on paraoxon and chlorpyrifos oxon toxicity in adult rats. G-protein receptor kinase (GRK)-dependent phosphorylation of M2 receptors initiates receptor desensitization, internalization and down-regulation. Studies in Aim 4 will test the hypothesis that some OP toxicants differentially alter GRK-mediated phosphorylation of M2 receptors leading to selective changes in receptor regulation. These studies should clarify the selective effects of OP insecticides on acetylcholine release/autoreceptor function in vivo, determine the relative role of autoreceptor function in age-related sensitivity, and evaluate whether alteration of GRK-mediated M2 regulatory pathways contribute to the selective modulation of muscarinic autoreceptor function by some OP toxicants.

描述(申请人提供)：有机磷(OP)抗胆碱酯酶的毒性机制涉及的步骤可能会受到一些步骤的选择性影响，为区分毒性提供了基础。乙酰胆碱的释放和抑制的M受体对乙酰胆碱的调节可能在OP毒物选择性毒性中起关键作用。一些抗胆碱酯酶(包括对硫磷和毒死蜱的氧离子，即对氧磷和毒死蜱氧磷)直接与M受体M2受体相互作用，M受体是M M受体的亚型。用超融合脑片测量乙酰胆碱释放，发现对氧磷和毒死蜱体外作用的定性差异，以及体内暴露对硫磷和毒死磷后M胆碱受体功能改变的时间差异。假设M受体功能是胆碱能毒性的重要修饰物，选择性调节或与年龄相关的活性差异可导致不同的毒性。目的1利用微透析技术比较对硫磷和毒死蜱对大鼠体内胆碱能毒性和乙酰胆碱释放的剂量相关效应。老年大鼠似乎对毒死蜱和对硫磷的急性影响更敏感。AIM 2的研究将评估乙酰胆碱释放/自身受体功能是否可能有助于与衰老有关的OP杀虫剂毒性的差异。目的3评价预先调节自身受体功能(通过注入自身受体激动剂、拮抗剂或M2受体反义)对对氧磷和毒死蜱毒性的影响。依赖于G蛋白受体激酶(GRK)的M2受体的磷酸化启动了受体的脱敏、内化和下调。目标4中的研究将检验这样一种假设，即一些OP毒物不同地改变GRK介导的M2受体的磷酸化，导致受体调节的选择性变化。这些研究应阐明OP杀虫剂对体内乙酰胆碱释放/自身受体功能的选择性作用，确定自身受体功能在年龄相关敏感性中的相对作用，并评估GRK介导的M2调节通路的改变是否有助于某些OP毒物选择性地调节M受体功能。