The role of SUR1 in synaptic and secretory vesicle function

我们都熟悉机器是由电驱动的这一事实，但可能没有那么多人意识到我们自己也是如此。你阅读和理解这一页的能力，看和听的能力，思考和说话的能力，以及移动你的胳膊和腿的能力，都是由于在你大脑的神经细胞和四肢的肌肉细胞中发生的电事件。反过来，这种电活动是由嵌入在每个细胞膜上的微小蛋白质孔（称为离子通道）发起和调节的。神经细胞被用来在全身传递电信号。在我们的大脑中，数十亿的神经细胞也在进行持续的电子对话，指导我们所有的思想和行动。但是神经细胞之间并没有物理上的联系，电脉冲也不能跳过它们之间的间隙。相反，一种被称为神经递质的化学信使被用来将信号从一个细胞传递到另一个细胞。传递发生在称为突触的特殊连接处，在那里两个神经细胞靠近在一起，它们之间的间隙非常小。在突触处，神经细胞的尖端密集地挤满了充满神经递质的膜结合小泡，当电脉冲到达神经末梢时，它会使小泡将其内容物释放到两个细胞之间的间隙中。然后神经递质通过间隙扩散并刺激下一个细胞的电脉冲。类似的过程也发生在腺体细胞中，它们将激素释放到血液中。这个过程还包括将激素包装成小泡，然后与细胞表面膜融合，当腺体细胞受到刺激时，将其内容物排入血液。然后，这些激素通过血液在体内循环，到达它们的目标器官。神经工作的方式，它们如何在突触上相互交流，以及离子通道在这个过程中的作用在《生命的火花》中得到了解释，这是一本由该资助的申请人之一（弗朗西斯·阿什克罗夫特）为普通读者写的书。这个项目的重点是控制神经末梢和腺体细胞释放囊泡的精确方式。我们对被称为KATP通道的离子通道特别感兴趣。它在调节血糖水平方面起着非常重要的作用，因为它控制着胰腺β细胞中激素胰岛素的释放。它在大脑的神经细胞中也很重要，而KATP通道基因突变的人不仅会患糖尿病，还可能会延迟发育。我们的初步数据表明，构成KATP通道的一种蛋白质在调节神经和腺体细胞的囊泡功能和释放方面具有新的作用。虽然我们几年前就知道这种蛋白质（称为SUR1）存在于胰岛素分泌囊泡中，但我们仍然不完全了解它在那里的作用。最近，随着我们发现SUR1也存在于大脑神经末梢的囊泡中，这个谜团加深了。因此，该基金的目的是了解SUR1在突触和分泌囊泡中的作用。这个问题具有相当重要的科学意义，因为它解决了一个基本问题——细胞是如何相互交流的？这对制药行业也很重要，因为许多临床上重要的药物会影响突触功能和激素释放。阐明SUR1参与的分子途径可能会为药物开发带来新的靶点。最后，我们建议使用的方法是新颖的，将导致科学家研究囊泡功能的新工具的发展。此外，我们正在与一家英国公司合作，为他们的显微镜开发新的应用。

We're all familiar with the fact that machines are powered by electricity, but it's perhaps not so widely appreciated that the same is true for ourselves. Your ability to read and understand this page, to see and hear, to think and speak, and to move your arms and legs is due to the electrical events taking place in the nerve cells in your brain and the muscle cells in your limbs. And, in turn, that electrical activity is initiated and regulated by tiny protein pores embedded in the membranes of each one of your cells, known as ion channels.Nerve cells are used to transmit electrical signals round the body. Within our brains, billions of nerve cells also engage in a constant electrical conversation, directing all our thoughts and actions. But nerve cells are not physically connected to one another and the electrical impulse cannot jump the gap between them. Instead a chemical messenger, known as a neurotransmitter, is used to send signals from one cells to another. Transmission takes place at specialised junctions called synapses, where the two nerve cells come close together and the gap between them is very tiny. At the synapse, the tip of the nerve cell is densely packed with small membrane-bound vesicles filled with neurotransmitter, and when an electrical impulse arrives at the nerve terminal it causes the vesicles to release their contents into the gap between the two cells. The neurotransmitter then diffuses across the gap and stimulates an electrical impulse in the next cell. A similar process takes place in gland cells, which release hormones into the blood stream. This process also involves the packaging of the hormone into tiny vesicles which then fuse with the surface membrane of the cell and empty their contents into the bloodstream when the gland cell is stimulated. The hormones then travel around the body in the blood to their target organs. The way in which nerves work, how they talk to one another at synapses, and the role of ion channels in this process is explained in The Spark of Life, a book for the general reader written by one of the applicants of this grant (Frances Ashcroft). This project is focused on the precise way in which the release of vesicles from nerve endings and gland cells is controlled. We are particularly interested in an ion channel known as KATP channel. It plays a very important role in the regulation of blood glucose levels because it controls the release of the hormone insulin from the beta-cells of the pancreas. It also is important in the nerve cells of the brain, and people with mutations in KATP channel genes not only get diabetes but may also have delayed development. Our preliminary data suggests that one of the proteins that makes up the KATP channel has a novel role in regulating vesicle function and release in both nerve and gland cells. Although we have known for some years that this protein (called SUR1) is present in the insulin secretory vesicles, we still don't fully understand what it does there. Recently, the mystery has deepened, as we discovered SUR1 is also present in vesicles at nerve endings in the brain. The aim of the grant is therefore to understand the role of SUR1 in both the synaptic and secretory vesicles. This question is of considerable scientific importance as it addresses a fundamental topic - how do cells communicate with one another? It is also of importance to the pharmaceutical industry because many clinically important drugs influence synaptic function and hormonal release. Elucidating the molecular pathways in which SUR1 is involved may lead to new targets for drug development. Finally, the methods that we propose to use are novel and will lead to the development of a new tool for scientists studying vesicle function. In addition, we are collaborating with a UK company to generate new applications for their microscopes.