Lynx in organization and dynamics of nicotinic acetylcholine receptor complexes

描述(由申请人提供)：烟碱型乙酰胆碱受体复合体的组织和动力学中的Lynx通道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。它们可以是遗传的，也可以是自身免疫反应产生的。烟碱型乙酰胆碱受体(NAChRs)的错误调节与神经疾病有关，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，在疾病状态下，nAChRs的数量和定位会发生变化，恢复其正确的数量和分布可以改善疾病表型。突触与突触外区域的定位也是nAChR功能的一个重要方面。Lynx蛋白是广泛表达的尼古丁受体功能的调节因子。去除lynx1基因会导致nAChR超敏反应，增强学习能力，延长双眼选择性的临界期，但也会导致神经变性。遗传学、生化和生理学研究表明，17和1422个nAChRs之间存在直接或间接的相互作用。Lynx蛋白与蛇和蜗牛的可溶性nAChR配体、1-银环蛇毒素和相关毒素具有(A)GPI锚点和(B)结构和功能上的相似性。GPI锚定的膜蛋白可以通过与有序的富含胆固醇的结构域和纳米结构域的优先结合来影响表面受体的分布和迁移率，这些结构域在质膜上积累了信号分子和细胞骨架成分。这些分子事件可以改变微环境，影响细胞表面受体的分布和寿命。因此，本项目研究了Lynx-nAChR相互作用对nAChR转运到质膜的机制、nAChRs在质膜上的分布、表面nAChRs的内化机制以及与细胞骨架和转运机制的潜在相互作用的影响。

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.