The dynamics of rapsyn in vitro and in vivo

rapsyn 的体外和体内动力学

• 批准号: 7283099
• 负责人: EMILE G BRUNEAU
• 金额: $ 2.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-05 至 2008-04-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283099
• 关键词: AMPA Receptors; Affect; Affinity; Animals; Behavior; Binding; Bungarotoxins; Chimeric Proteins; Cholinergic Receptors; Chromosome Pairing; Confocal Microscopy; Cytoskeleton; DLG4 gene; Excision; Fellowship; Fluorescence; Fluorescence Recovery After Photobleaching; GABA Receptor; Genes; Glycine; Green Fluorescent Proteins; Human; In Vitro; Individual; Knock-out; Knowledge; Life; Ligands; Link; Maintenance; Mediating; Methods; Monitor; Mus; Muscle; Muscle Fibers; Muscular Dystrophies; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; Names; Neuromuscular Diseases; Neuromuscular Junction; Numbers; Point Mutation; Proteins; Range; Rate; Regulation; Resolution; Scaffolding Protein; Snakes; Specificity; Sternocleidomastoid Muscle; Synapses; Synaptic plasticity; Techniques; Time; Toxin; Work; alpha-dystrobrevin; cholinergic synapse; density; extracellular; gephyrin; in vivo; interest; peripheral membrane protein 43K; postsynaptic; presynaptic density protein 95; promoter; receptor; receptor density; receptor function; scaffold; synaptic function; synaptogenesis; therapy development; trafficking

DESCRIPTION (provided by applicant): The main objective of this study is to determine the dynamics and intracellular trafficking of the acetylcholine receptor associated protein, rapsyn. Rapsyn is the only intracellular protein known to bind directly to acetylcholine receptors, and is functionally analogous to a number of other receptor associated proteins such as PSD-95 (which binds to NMDA receptors), GRIP (which binds to AMPA receptors) and gephyrin (which binds to glycine and GABA receptors). Rapsyn is known to be essential to receptor clustering and synapse formation, as knockouts of rapsyn in mice are lethal, and single point mutations in the rapsyn gene or promoter are able to cause severe muscular dystrophies in humans. Since rapsyn is intimately associated with AChRs and is crucial for proper receptor localization, it will be of great interest to gain an understanding of rapsyn dynamics and trafficking in comparison to AChRs. The results of these studies may also help us to better understand the dynamics of analogous proteins that are involved in synaptic plasticity at less accessible central synapses. In addition, many neuromuscular diseases present alterations in post-synaptic scaffolding proteins. By investigating the behavior of these proteins we may therefore be able to define new avenues for the development of therapies for neuromuscular disease.

描述（由申请方提供）：本研究的主要目的是确定乙酰胆碱受体相关蛋白rapsyn的动力学和细胞内运输。Rapsyn是已知直接结合乙酰胆碱受体的唯一细胞内蛋白，并且在功能上类似于许多其他受体相关蛋白，例如PSD-95（其结合NMDA受体）、GRIP（其结合AMPA受体）和桥蛋白（其结合甘氨酸和GABA受体）。已知Rapsyn对受体聚集和突触形成至关重要，因为小鼠中Rapsyn的敲除是致命的，并且rapsyn基因或启动子中的单点突变能够在人类中引起严重的肌营养不良症。由于rapsyn与AChRs密切相关，并且对于适当的受体定位至关重要，因此与AChRs相比，了解rapsyn动力学和贩运将非常有趣。这些研究的结果也可能帮助我们更好地理解类似蛋白质的动力学，这些蛋白质在较难接近的中央突触中参与突触可塑性。此外，许多神经肌肉疾病存在突触后支架蛋白的改变。通过研究这些蛋白质的行为，我们可能因此能够为神经肌肉疾病的治疗方法的发展确定新的途径。