Role of vesicular TRPM7 channels in synaptic vesicle endocytosis

囊泡 TRPM7 通道在突触小泡内吞作用中的作用

• 批准号: 10133166
• 负责人: Liang-Wei Gong
• 金额: $ 34.39万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133166
• 关键词: Acetylcholine; Action Potentials; Affinity; Alzheimer' s Disease; Anoxia; Area; Biochemical; Biological Assay; Biophysics; Brain; C-terminal; Cations; Cell membrane; Cells; Charge; Chromaffin Cells; Data; Defect; Development; Disease; Electric Capacitance; Endocytic Vesicle; Endocytosis; Epilepsy; Etiology; Exocytosis; Functional disorder; Glutamates; Goals; Human; Ischemia; Kinetics; Knock-out; Knowledge; Lead; Link; Literature; Mental Depression; Mission; Modeling; Molecular; Molecular Biology Techniques; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurons; Neurotransmitters; Parkinson Disease; Pathogenesis; Pathway interactions; Permeability; Phosphotransferases; Physiological; Process; Proteins; Public Health; Publishing; Recycling; Research; Role; Route; Synaptic Vesicles; Temperature; Testing; Time; United States National Institutes of Health; Vesicle; Work; base; disability; gamma-Aminobutyric Acid; live cell imaging; mutant; neuron loss; novel therapeutics; patch clamp; presynaptic; response; risk prediction

Summary TRPM7, a Ca2+ permeable nonselective cation channel, is linked to neurodegenerative diseases, and a human TRPM7 mutation has been identified in Parkinson's diseases (PD), suggesting its critical role in neurodegeneration. Published work has implied that neuronal death during anoxia and ischemia may be attributed to Ca2+ overflow via TRPM7. However, roles of TRPM7 in neurons remain undefined at physiological conditions. Biochemical studies demonstrate that TRPM7 is concentrated on synaptic vesicles and interacts with vesicular proteins, indicating that TRPM7 may be a critical player in synaptic vesicle recycling. Although vesicular TRPM7 may provide counterions for release of positively charged acetylcholine during exocytosis in sympathetic neurons, TRPM7 is also widely distributed in areas with negatively charged glutamate and neutral GABA as dominant neurotransmitters, suggesting a separate function in these regions. Therefore, the physiological function of presynaptic TRPM7 in the brain remains largely unknown. Our preliminary data presented in the research strategy strongly suggest that TRPM7 is the main conduit for Ca2+ influx in endocytosis, leading us to hypothesize that vesicular TRPM7 serves as the Ca2+ channel for synaptic vesicle endocytosis. We will test this hypothesis by using a combination of biophysical, live-cell imaging, and molecular biology techniques. Our goal is to clearly define, for the first time, the role of TRPM7 in endocytosis. Our studies will have profound implications for understanding the mechanisms of normal neuronal endocytic processes, how dysfunctions in these processes lead to neurodegenerative disease, and for development of new therapies to treat diseases with malfunctions in synaptic vesicle recycling and/or TRPM7.

概括 TRPM7是CA2+渗透性非选择性阳离子通道，与神经退行性疾病有关 在帕金森氏病（PD）中已经确定了TRPM7突变，这表明其在 神经变性。已发表的工作暗示着在缺氧和缺血期间的神经元死亡可能是 通过TRPM7归因于Ca2+溢出。然而，TRPM7在神经元中的作用在生理上仍然不确定 状况。生化研究表明，TRPM7集中在突触囊泡上并相互作用 使用囊泡蛋白，表明TRPM7可能是突触囊泡回收的关键参与者。虽然 囊泡TRPM7可以提供反胞外胞吐期间带正电乙酰胆碱释放的反替代品 交感神经元，TRPM7也被广泛分布在带负电荷的谷氨酸和中性的区域 GABA是主要的神经递质，在这些区域表明了单独的功能。因此， 大脑中突触前TRPM7的生理功能在很大程度上未知。 我们在研究策略中介绍的初步数据强烈表明TRPM7是主要渠道 CA2+内吞作用中的流入，导致我们假设囊泡TRPM7是Ca2+通道 突触囊泡内吞作用。我们将通过使用生物物理，活细胞的组合来检验该假设 成像和分子生物学技术。 我们的目标是首次明确定义TRPM7在内吞作用中的作用。我们的研究将有深远的 理解正常神经元内吞作用的机制的含义 这些过程导致神经退行性疾病，并开发用于治疗疾病的新疗法 突触囊泡回收和/或TRPM7的故障。