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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.

突触神经元之间的有效通信是大脑正常功能所必需的。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。该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，对于一种称为红藻氨酸受体的受体，递质的结合会导致一种称为 SUMO 的小蛋白质附着，这导致受体通过一种称为内吞作用的机制从表面移入细胞（在那里它不再发挥作用）。防止 SUMO 附着到红藻氨酸受体上会阻止内吞作用。我们继续证明这个过程调节神经元之间的通信。这很重要，因为红藻氨酸受体调节神经元和突触传递的总体兴奋性，并且它们的功能障碍与癫痫和亨廷顿病等疾病有关。此外，我们还发现，除了我们所表征的受体之外，突触中还存在许多其他蛋白质，它们也经历了类似的 SUMO 添加。该提案的目的是继续研究该流程如何运作的一些细节。具体来说，我们想找出受体中的哪些变化使其能够结合 SUMO，以及受体被 SUMO 化后会发生哪些分子变化。我们相信这些实验对于理解突触如何发挥作用具有非常重要的意义。此外，一旦我们阐明了红藻氨酸受体在正常细胞中的处理方式，我们就可以深入了解受伤或患病细胞中发生的情况，并尝试制定策略来补偿或修复问题。