Molecular mechanisms and synaptic functions of kainate receptor SUMOylation

突触中神经元之间的有效交流是大脑正常运作所必需的。这种交流使用化学递质，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取决于突触的活动。我们发现，对于一种叫做盐酸盐受体的受体，与递质的结合会导致一种叫做SUMO的小蛋白质的附着，这导致受体通过一种叫做内吞作用的机制从表面被移到细胞中（在那里它不再起作用）。阻止SUMO附着于盐酸盐受体可阻断内吞作用。我们继续证明这个过程调节神经元之间的交流。这是很重要的，因为盐酸盐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，我们表明，除了我们所描述的受体，还有许多其他蛋白质存在于突触中，经历类似的SUMO添加。本提案的目的是继续解决这个过程如何工作的一些细节。具体来说，我们想要找出受体的什么变化允许它与SUMO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有非常重要的意义。此外，一旦我们阐明了在正常细胞中如何处理盐酸盐受体，我们就可以深入了解受伤或患病细胞中发生了什么，并试图制定补偿或修复问题的策略。

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.