Role of vesicular TRPM7 channels in synaptic vesicle endocytosis

总结 TRPM 7是一种Ca 2+渗透性非选择性阳离子通道，与神经退行性疾病有关， TRPM 7突变已在帕金森病（PD）中被鉴定，表明其在帕金森病中的关键作用。 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 这归因于通过TRPM 7的Ca 2+溢出。然而，TRPM 7在神经元中的作用在生理学上仍然不确定。 条件生物化学研究表明，TRPM 7集中在突触囊泡上，并与突触囊泡相互作用。 与囊泡蛋白，表明TRPM 7可能是突触囊泡回收的关键球员。虽然 囊泡TRPM 7可能在胞吐过程中为带正电荷的乙酰胆碱的释放提供反离子。 在交感神经元中，TRPM 7也广泛分布在具有带负电荷的谷氨酸和中性谷氨酸的区域中。 GABA作为主要的神经递质，这表明在这些地区的独立功能。因此 突触前TRPM 7在脑中的生理功能在很大程度上仍然未知。 我们在研究策略中提出的初步数据强烈表明，TRPM 7是 内吞作用中的Ca 2+内流，使我们假设囊泡TRPM 7作为Ca 2+通道， 突触囊泡内吞作用。我们将通过使用生物物理，活细胞， 成像和分子生物学技术。 我们的目标是首次明确TRPM 7在内吞作用中的作用。我们的研究将对 理解正常神经元内吞过程的机制， 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。 突触囊泡再循环和/或TRPM 7功能障碍。

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.