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Molecular mechanisms and synaptic functions of kainate receptor SUMOylation

红藻氨酸受体SUMO化的分子机制和突触功能

基本信息

批准号：
BB/F00723X/1
负责人：
Jeremy Henley
金额：
$ 120.71万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FF00723X%2F1
关键词：
Molecular mechanisms synaptic functions kainate

项目摘要

Efficient communication between neurones at synapses is required for proper brain function. This communication uses chemical transmitters and relies on the presence of receptor proteins at the synapse surface. A key feature of this system is that the number of receptors changes depending on the activity at the synapse. We have found that for one type of receptor called the kainate receptor, binding of the transmitter leads to attachment of a small protein called SUMO and this results in the receptor being removed from the surface into the cell (where it can no longer function) by a mechanism called endocytosis. Preventing SUMO attachment to kainate receptors blocks endocytosis. We go on to demonstrate that this process regulates communication between neurones. This is significant because kainate receptors regulate the general excitability of neurones and synaptic transmission and their dysfunction has been implicated in diseases such as epilepsy and Huntington's disease. In addition, we show that in addition to the receptor we have characterised, there are many other proteins present at synapses that undergo similar addition of SUMO. The aim of this proposal is to go on to work out some of the details of how this process works. Specifically we want to find out what change in the receptor allows it to bind SUMO and what molecular changes take place once the receptor is SUMOylated. We believe these experiments will have very important implications for understanding how synapses function. Furthermore, once we shed light on how kainate receptors are handled in normal cells we can then gain insight into what happens in injured or diseased cells and try to formulate strategies to compensate for or repair the problems.

突触上神经元之间的有效沟通是正常大脑功能所必需的。这种通讯使用化学递质，并依赖于突触表面受体蛋白的存在。这个系统的一个关键特征是受体的数量根据突触的活动而变化。我们发现，对于一种名为海人酸受体的受体，受体的结合会导致一种名为相扑的小蛋白的附着，这会导致受体通过一种称为内吞作用的机制从表面移入细胞(在那里它不能再起作用)。防止相扑附着在海人酸受体上会阻止内吞作用。我们继续证明，这一过程调节神经元之间的交流。这一点意义重大，因为海人藻酸受体调节神经元的一般兴奋性和突触传递，其功能障碍与癫痫和亨廷顿病等疾病有关。此外，我们还表明，除了我们描述的受体外，突触中还有许多其他蛋白质经历了类似的相扑添加。这项提议的目的是继续制定这一过程如何运作的一些细节。具体地说，我们想找出受体的什么变化允许它与相扑结合，以及一旦受体被SUMO化，会发生什么分子变化。我们相信，这些实验将对理解突触的功能具有非常重要的意义。此外，一旦我们弄清楚了红藻氨酸受体在正常细胞中是如何处理的，我们就可以深入了解在受损或患病的细胞中发生了什么，并试图制定出补偿或修复问题的策略。