The function of dynamin phosphorylation sites in synaptic vesicle endocytosis

动力蛋白磷酸化位点在突触小泡内吞作用中的功能

• 批准号: nhmrc : 423403
• 负责人: Prof Phillip Robinson
• 金额: $ 52.98万
• 依托单位: Children's Medical Research Institute
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/function-dynamin-phosphorylation-vesicle-endocytosis/98943
• 关键词: function; dynamin; phosphorylation; sites; synaptic

Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when endocytosis cannot keep up then exocytosis slows, greatly reducing the function of neurons. A complete block would result in paralysis of brain and muscles. Our team has been revealing the underlying molecular mechanisms of endocytosis in order to better understand diseases of the synapse like schizophrenia, epilepsy and Alzheimer's disease. We discovered that endocytosis is a regulated process at the heart of which is a pair of phosphorylation sites (points of phosphate attachment) in the key protein dynamin I. Our hypothesis is that endocytosis occurs in two forms, fast and slow. We propose to test the idea that proteins that associate with dynamin via the phosphorylation sites determine whether the fast or slow mode is used. Additionally, we propose that the first phosphorylation site is the trigger for endocytosis, while the second serves to recruit reserve supplies of dynamin to support the slow mode when it's required. A better understanding of Dyn and endocytosis is crucial to understanding brain disorders of synaptic transmission and ultimately for developing therapies. For example, a seizure is the uncontrolled firing of neurons. Our overall aim is to understand the control mechanisms of nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy.

神经元通过释放神经递质相互交流，神经递质被包装在神经末梢内的突触小泡中。囊泡的数量是有限的，因此它们被回收（内吞作用）以供重复使用。突触小泡的胞吐作用非常快，通常胞吞作用稍慢一些，从而清除使用过的小泡。最近我们发现内吞作用可以控制突触传递，因此它是突触传递整个周期的一个组成部分。我们发现，当内吞作用无法跟上时，胞吐作用就会减慢，从而大大降低神经元的功能。完全阻塞会导致大脑和肌肉瘫痪。我们的团队一直在揭示内吞作用的潜在分子机制，以便更好地了解突触疾病，如精神分裂症、癫痫和阿尔茨海默病。我们发现内吞作用是一个受调节的过程，其核心是关键蛋白动力 I 中的一对磷酸化位点（磷酸盐附着点）。我们的假设是内吞作用以两种形式发生：快速和慢速。我们建议测试以下想法：通过磷酸化位点与动力蛋白结合的蛋白质决定是否使用快速或慢速模式。此外，我们建议第一个磷酸化位点是内吞作用的触发器，而第二个磷酸化位点则用于招募动力储备供应以在需要时支持慢速模式。更好地理解 Dyn 和内吞作用对于理解突触传递的大脑疾病以及最终开发治疗方法至关重要。例如，癫痫发作是神经元不受控制的放电。我们的总体目标是了解神经通讯的控制机制，最终使我们能够治疗癫痫等神经通讯疾病。