MOLECULAR CHARACTERIZATION OF MUSCARINIC ACH RECEPTORS

毒蕈碱 ACH 受体的分子表征

• 批准号: 3402168
• 负责人: WILLIAM L KLEIN
• 金额: $ 12.65万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-23 至 1993-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3402168
• 关键词: affinity chromatography; autoradiography; biological signal transduction; chemical binding; chickens; cow; electron microscopy; gel electrophoresis; gene expression; genetic library; genetic transcription; genetic translation; glycosylation; histochemistry /cytochemistry; hybridomas; immunochemistry; ligands; molecular weight; monoclonal antibody; muscarinic receptor; neural conduction; neural information processing; neural plasticity; neurogenesis; posttranslational modifications; protein sequence; protein structure function; receptor expression; synapses

A 5-year molecular-level strategy is proposed for attacking an important problem in vertebrate neurodevelopment: "How do CNS neurons create postsynaptic zones specialized for proper signal transduction?" The elementary activity of the brain is signaling between cells -- mechanisms underlying development, maintenance and plasticity of signal transduction are at the foundation of brain function. Muscarinic acetylcholine receptors have been selected as prototypes for studying CNS postsynaptic specialization. These receptors are implicated in a host of physiological and behavioral processes, including conscious arousal, learning and memory. Moreover, because Alzheimer's disease is associated with the death of ACh- containing cells, new studies of cholinoceptive postsynaptic cells could have considerable relevance to the public health. The proposed work pursues fundamental questions stimulated by three significant discoveries: (1) The CNS (but not heart) expresses a novel 86 kDa "embryonic" type MAChR, abundant during neurite growth, that developmentally down-regulates and is supplanted by a 72 kDa "adult type" molecules; (2) In vivo, neurons stringently regulate the placement of receptors, with all molecules localized to dendrites even before synapses have formed; (3) Developing neurons are "plastic" with respect to receptor placement and expression of 86K/72K molecular types. These new and important observations were made in studies of the chicken CNS, a widely-used model for vertebrate neurodevelopment. Three specific aims have been selected as most critical for expanding these findings: (1) To establish the origin and structure of the 86 kDa and 72 kDa receptor molecules by characterizing chicken receptor genes and their transcription in the developing CNS. (2) To determine where the 86K and 72K molecules are localized relative to synaptic junctions, assessing possible mechanisms underlying placement and plasticity. (3) To compare the function of 86K and 72K receptors, investigating possible novel growth-associated roles during the period of neurite arborization and synaptogenesis.

提出了一个为期 5 年的分子水平战略来攻击 脊椎动物神经发育的一个重要问题：“中枢神经系统如何 神经元创建专门用于正确信号的突触后区域 转导？”大脑的基本活动是信号传导 细胞之间——发育、维持的机制 信号转导的可塑性和可塑性是 大脑功能。 毒蕈碱乙酰胆碱受体已被选为原型 用于研究中枢神经系统突触后专门化。 这些受体是 涉及许多生理和行为过程， 包括有意识的唤醒、学习和记忆。 而且， 因为阿尔茨海默病与乙酰胆碱的死亡有关 含有细胞，胆碱感受性突触后细胞的新研究 可能与公共卫生有很大关系。 拟议的工作追求由三个问题引发的基本问题 重大发现：（1）中枢神经系统（但不是心脏）表达 新颖的 86 kDa“胚胎”型 MAChR，在神经突期间丰富 生长，在发育过程中下调并被取代 72 kDa“成人型”分子； (2)在体内，神经元严格 调节受体的位置，所有分子都定位 甚至在突触形成之前就形成树突； (3) 开发中 神经元在受体位置方面是“可塑的” 86K/72K 分子类型的表达。 这些新的、重要的 在对鸡中枢神经系统的研究中进行了观察，鸡中枢神经系统是一种广泛使用的神经系统。 脊椎动物神经发育模型。 制定了三个具体目标 被选为扩展这些发现最关键的： (1) 确定86 kDa和72 kDa的起源和结构 通过表征鸡受体基因和受体分子 它们在发育中的中枢神经系统中的转录。 (2) 确定86K和72K分子的定位位置 相对于突触连接，评估可能的机制 底层布局和可塑性。 (3)比较86K和72K受体的功能，研究 神经突期间可能具有与生长相关的新作用 树枝化和突触发生。