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

基本信息

批准号：
10374820
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
项目类别：
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/10374820
关键词：
Acetylcholine Action Potentials Affinity Alzheimer&apos 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

项目摘要

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 是一种 Ca2+ 渗透性非选择性阳离子通道，与神经退行性疾病有关，并且人类 TRPM7 突变已在帕金森病 (PD) 中被发现，表明其在帕金森病 (PD) 中发挥着关键作用神经变性。已发表的研究表明，缺氧和缺血期间的神经元死亡可能是归因于通过 TRPM7 的 Ca2+ 溢出。然而，TRPM7 在神经元中的作用在生理学上仍然不明确。状况。生化研究表明 TRPM7 集中在突触小泡上并相互作用与囊泡蛋白的结合，表明 TRPM7 可能是突触囊泡回收的关键参与者。虽然囊泡 TRPM7 可能为胞吐作用期间释放带正电荷的乙酰胆碱提供抗衡离子交感神经元中，TRPM7也广泛分布于带负电的谷氨酸和中性带电的区域 GABA 作为主要神经递质，表明这些区域具有独立的功能。因此，大脑中突触前 TRPM7 的生理功能仍然很大程度上未知。我们在研究策略中提供的初步数据强烈表明 TRPM7 是内吞作用中 Ca2+ 流入，使我们推测囊泡 TRPM7 作为 Ca2+ 通道突触小泡内吞作用。我们将通过使用生物物理、活细胞的组合来检验这一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。我们的研究将会产生深远的影响对于理解正常神经元内吞过程的机制、功能障碍如何这些过程导致神经退行性疾病，并用于开发治疗疾病的新疗法突触小泡回收和/或 TRPM7 出现故障。