The function of dynamin phosphorylation sites in synaptic vesicle endocytosis

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的突触囊泡中。由于囊泡的数量有限，所以它们被循环利用（内吞作用）。突触囊泡胞吐非常快，正常情况下胞吞作用稍慢，将使用过的囊泡清除。最近我们发现内吞作用可以控制突触传递，因此它是整个突触传递周期的一个组成部分。我们发现，当胞吞作用跟不上时，胞吐作用就会减慢，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，以便更好地了解像精神分裂症、癫痫和阿尔茨海默病这样的突触疾病。我们发现内吞作用是一个受调控的过程，其核心是关键蛋白动力蛋白i上的一对磷酸化位点（磷酸盐附着点）。我们的假设是内吞作用以两种形式发生，快速和缓慢。我们提议测试这样一种观点，即通过磷酸化位点与动力蛋白相关联的蛋白质决定了是使用快模式还是慢模式。此外，我们提出第一个磷酸化位点是内吞作用的触发点，而第二个磷酸化位点则是在需要时招募动力蛋白的储备供应来支持慢速模式。更好地了解Dyn和内吞作用对于理解突触传递的大脑疾病并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交流的控制机制，最终使我们能够治疗神经交流障碍，如癫痫。

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.