STRUCTURE OF INSECT NEUROTRANSMITTER RECEPTORS

昆虫神经递质受体的结构

• 批准号: 3144384
• 负责人: JAMES A NATHANSON
• 金额: $ 19.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-03-01 至 1995-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3144384
• 关键词: G protein; adenylate cyclase; arthropod nonpollutant control; chemical binding; dopamine receptor; enzyme induction /repression; inhibitor /antagonist; mites; molecular cloning; neurotransmitter receptor; octopamine; protein structure function; receptor expression; serotonin receptor; site directed mutagenesis

Insects and acarines (mites, ticks) are vectors for a variety of infectious diseases (e.g., Lyme disease, malaria, equine encephalitis, Rocky Mountain spotted fever, typhus, yellow fever) in addition to being major agricultural pests. Many current pesticides and acaricides act at receptors and ion channels in the nervous systems of arthropods but, unfortunately, because they lack specificity, these pesticides also have significant side effects on the mammalian nervous system. In order to develop highly selective pesticides and acaricides, much more needs to be known about the structure and pharmacology of insect and acarine hormone and neuro-transmitter receptors, particularly those which appear from corresponding receptors in mammals. Using molecular biology techniques which have been so successful in elucidating the structure of vertebrate adrenergic receptors, this grant proposes to clone, from insects and acarines, the family of receptors for octopamine (thought to be the invertebrate analog to norepinephrine) and, subsequently, the receptor proteins for dopamine and serotonin (which may differ pharmacologically from their vertebrate counterparts). Cloning of octopamine receptors will be facilitated by recent advances in the Principal Investigator's Laboratory which have led to the development of a novel, selective, and highly potent octopamine photoaffinity ligand and the use of this ligand to purify an octopamine receptor protein. An alternative cloning strategy based upon homology to mammalian adrenergic receptors will also be used. Once isolated, the structures and pharmacology of these invertebrate amine receptors will be studied in great detail, through sequencing, site-directed mutagenesis and eukaryotic expression. The homology of these receptors to vertebrate amine receptors will be determined and the distribution of receptors and subtypes, in insects and acarines (and possibly other phylla of medical significance), will be determined for various species, tissues, and developmental stages, thereby providing a rational basis for the development of selective aminergic pesticides and acaricides.

昆虫和杏仁碱（螨虫，tick虫）是各种传染性的媒介 疾病（例如莱姆病，疟疾，马脑炎，落基山 除了主要 农业害虫。 许多当前的农药和抗磷脂作用 节肢动物神经系统中的受体和离子通道，但 不幸的是，由于它们缺乏特异性，这些农药也有 对哺乳动物神经系统的显着副作用。 为了 开发高度选择性的农药和丙帕酰胺，需要更多 关于昆虫和杏仁激素的结构和药理学已知 和神经递质受体，尤其是从 哺乳动物中的相应受体。 使用在 阐明脊椎动物肾上腺素能受体的结构，该赠款 提议克隆，从昆虫和障碍物中，受体家族 章鱼胺（被认为是对去甲肾上腺素的无脊椎动物类似物），并且 随后，多巴胺和5-羟色胺的受体蛋白（可能 药理学与脊椎动物的差异不同）。 克隆 章鱼受体将在最近的进步方面促进 主要研究者的实验室，导致了 小说，选择性且高度有效的章鱼光性配体和 使用该配体纯化章鱼受体蛋白。 一个 基于哺乳动物肾上腺素的同源性的替代克隆策略 也将使用受体。 一旦孤立，结构和 这些无脊椎动物胺受体的药理学将在很大程度上研究 细节，通过测序，定向诱变和真核生物 表达。 这些受体与脊椎动物受体的同源性 将确定并在受体和亚型的分布中分布 昆虫和杏仁酸（可能是其他具有医学意义的叶兰）， 将针对各种物种，组织和发育阶段确定， 从而为开发选择性提供合理的依据 氨基化农药和抗磷脂剂。