Lynx in organization and dynamics of nicotinic acetylcholine receptor complexes

烟碱乙酰胆碱受体复合物的组织和动力学中的山猫

• 批准号: 8246947
• 负责人: Henry A. Lester
• 金额: $ 17.27万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246947
• 关键词: Abbreviations; Affect; Alzheimer' s Disease; Animals; Antibodies; Area; Autoimmune Process; Binding; Biochemical; Biology; Bungarotoxins; Cell membrane; Cell surface; Chimeric Proteins; Cholesterol; Cholinesterase Inhibitors; Clathrin; Complex; Data; Disease; Dynamin; Endocytosis; Endoplasmic Reticulum; Epidemiology; Epilepsy; Event; Excision; Exocytosis; Family Caregiver; Fluorescence; Fluorescence Resonance Energy Transfer; Functional disorder; Future; Genes; Genetic; Genus Lynx; Health; Homo; Hypersensitivity; Image; Imagery; Impaired cognition; In Vitro; India; Individual; Ion Channel; Joints; Knock-in Mouse; Knock-out; Label; Learning; Life; Ligands; Link; Lymphocyte antigen; Mammalian Cell; Measures; Membrane Proteins; Molecular; Mood Disorders; Muscarinics; Myasthenia Gravis; Nerve Degeneration; Neurologic; Neurons; Nicotine Dependence; Nicotinic Receptors; PHluorin; Parkinson Disease; Pathway interactions; Persons; Pharmaceutical Preparations; Physiological; Predisposition; Process; Productivity; Proteins; RNA Interference; Reaction; Recording of previous events; Regulation; Resolution; Schizophrenia; Signal Transduction; Signaling Molecule; Snails; Snakes; Sphingolipids; Surface; Synapses; Techniques; Testing; Tobacco use; Toxin; Urokinase; Vesicle; base; critical period; disease phenotype; drug discovery; fluorophore; improved; in vivo; latrunculin A; link protein; nanoscale; nervous system disorder; neuroprotection; neuropsychiatry; neurotransmitter release; receptor; receptor function; relating to nervous system; restoration; single molecule; therapeutic target; trafficking; trans-Golgi Network; transmission process

DESCRIPTION (provided by applicant): Lynx in organization and dynamics of nicotinic acetylcholine receptor complexes Channelopathies are diseases of ion channel dysfunction, arising either in channel proteins themselves or in associated proteins. They can arise either genetically or via autoimmune reaction. Mis-regulation of nicotinic acetylcholine receptors (nAChRs) is linked to neural disorders, including schizophrenia, some epilepsies, nicotine addiction, myasthenia gravis, Alzheimer's disease, and Parkinson's disease. Common findings are that the number and localization of nAChRs are altered during in the disease state, and that restoration of their correct number and distribution can ameliorate disease phenotypes. Localization in synaptic vs extrasynaptic areas is also a crucial aspect of nAChR function. Lynx proteins are widely expressed regulators of nicotinic receptor function. Removal of the lynx1 gene results in nAChR hypersensitivity, enhanced learning, and extended critical periods for binocular selectivity, but also susceptibility to neurodegeneration. Genetic, biochemical, and physiological studies indicate direct or indirect interactions between 17 and 1422 nAChRs. Lynx proteins have (a) GPI anchors and (b) structural and functional similarities to the soluble nAChR ligands, 1-bungarotoxin and related toxins from snakes and snails. GPI-anchored membrane proteins can influence the distribution and mobility of surface receptors, through their preferential association with well-ordered, cholesterol-rich domains and nanodomains that accumulate signaling molecules and cytoskeletal components at the plasma membrane. These molecular events can produce an altered microenvironment, influencing receptor distribution and lifetime at the cell surface. Therefore, this project investigates the effect of lynx-nAChR interactions on the mechanisms of nAChR trafficking to the plasma membrane, the distribution of nAChRs on the plasma membrane, the mechanisms of internalization of surface nAChRs, and the underlying interactions with cytoskeletal and trafficking machinery. PUBLIC HEALTH RELEVANCE: The worldwide health burden of neural disease is projected to increase 5-fold by year 2050, to >$1trillion/year. Optimal therapies do not yet exist for several neural diseases that involve nicotinic receptors: Alzheimer's disease, cognitive dysfunction, schizophrenia, nicotine addiction, some epilepsies, and myasthenia gravis. Nicotinic receptors are also promising targets for therapeutics, for instance in Parkinson's disease and mood disorders.

描述（由申请人提供）：Lynx在烟碱乙酰胆碱受体复合物的组织和动力学中的作用神经病是离子通道功能障碍的疾病，发生在通道蛋白本身或相关蛋白中。它们可以通过遗传或自身免疫反应产生。烟碱乙酰胆碱受体（nAChR）的错误调节与神经障碍有关，包括精神分裂症、一些癫痫、尼古丁成瘾、重症肌无力、阿尔茨海默病和帕金森病。常见的发现是nAChR的数量和定位在疾病状态期间改变，并且恢复其正确的数量和分布可以改善疾病表型。在突触与突触外区域的定位也是nAChR功能的一个重要方面。Lynx蛋白是烟碱受体功能的广泛表达调节剂。去除lynx 1基因会导致nAChR超敏反应，增强学习能力，延长双眼选择性的关键期，但也易患神经退行性疾病。遗传，生物化学和生理学研究表明17和1422 nAChRs之间的直接或间接的相互作用。Lynx蛋白具有（a）GPI锚和（B）与可溶性nAChR配体、1-银环蛇毒素和来自蛇和蜗牛的相关毒素的结构和功能相似性。GPI锚定的膜蛋白可以影响表面受体的分布和流动性，通过它们与有序的、富含胆固醇的结构域和纳米结构域的优先结合，这些结构域在质膜上积累信号传导分子和细胞骨架组分。这些分子事件可以产生改变的微环境，影响细胞表面的受体分布和寿命。因此，本项目研究lynx-nAChR相互作用对nAChR运输到质膜的机制、nAChR在质膜上的分布、表面nAChR内化的机制以及与细胞骨架和运输机制的潜在相互作用的影响。 公共卫生相关性：预计到2050年，全球神经疾病的健康负担将增加5倍，达到每年1万亿美元。对于涉及烟碱受体的几种神经疾病，目前还没有最佳的治疗方法：阿尔茨海默病、认知功能障碍、精神分裂症、尼古丁成瘾、某些癫痫和重症肌无力。烟碱受体也是治疗的有希望的靶标，例如在帕金森病和情绪障碍中。