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The role of SUR1 in synaptic and secretory vesicle function

SUR1 在突触和分泌囊泡功能中的作用

基本信息

批准号：
BB/R017220/1
负责人：
Frances Ashcroft
金额：
$ 61.28万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR017220%2F1
关键词：
role SUR1 synaptic secretory vesicle

项目摘要

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.

我们都知道机器是由电力驱动的，但可能没有那么广泛地认识到这对我们自己也是如此。你阅读和理解本页的能力，看和听，思考和说话，以及移动你的手臂和腿是由于你大脑中的神经细胞和四肢中的肌肉细胞中发生的电事件。反过来，电活动是由细胞膜上的微小蛋白质孔启动和调节的，这些蛋白质孔被称为离子通道。神经细胞用于在全身传递电信号。在我们的大脑中，数十亿个神经细胞也参与了持续的电子对话，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连接，电脉冲也不能跨越它们之间的差距。取而代之的是一种化学信使，称为神经递质，用于将信号从一个细胞发送到另一个细胞。信号的传递发生在称为突触的特殊连接处，在这里两个神经细胞靠得很近，它们之间的差距非常小。在突触处，神经细胞的尖端密集地堆积着充满神经递质的小膜囊泡，当电脉冲到达神经末梢时，它会使囊泡将其内容物释放到两个细胞之间的差距中。然后神经递质扩散穿过差距并刺激下一个细胞的电脉冲。类似的过程也发生在腺细胞中，腺细胞将激素释放到血液中。这个过程还包括将激素包装成微小的囊泡，然后与细胞的表面膜融合，并在腺细胞受到刺激时将其内容物排入血液。然后激素在血液中围绕身体移动到它们的目标器官。神经工作的方式，它们如何在突触上相互交谈，以及离子通道在这一过程中的作用，在《生命的火花》一书中得到了解释，这本书是由该基金的申请人之一（弗朗西斯·阿什克罗夫特）为普通读者撰写的。这个项目的重点是精确的方式，其中释放囊泡从神经末梢和腺细胞的控制。我们特别感兴趣的是一种被称为KATP通道的离子通道。它在血糖水平的调节中起着非常重要的作用，因为它控制着胰岛素从胰腺β细胞的释放。它在大脑的神经细胞中也很重要，KATP通道基因突变的人不仅会患糖尿病，而且可能会延迟发育。我们的初步数据表明，组成KATP通道的蛋白质之一在调节神经和腺细胞中的囊泡功能和释放方面具有新的作用。虽然我们已经知道这种蛋白质（称为SUR 1）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，这个谜团加深了，因为我们发现SUR 1也存在于大脑神经末梢的囊泡中。因此，该基金的目的是了解SUR 1在突触和分泌囊泡中的作用。这个问题具有相当大的科学重要性，因为它涉及一个基本的主题-细胞如何相互交流？它对制药工业也很重要，因为许多临床上重要的药物影响突触功能和激素释放。阐明SUR 1参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。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The KCNJ11-E23K Gene Variant Hastens Diabetes Progression by Impairing Glucose-Induced Insulin Secretion

KCNJ11-E23K 基因变异通过损害葡萄糖诱导的胰岛素分泌来加速糖尿病进展

DOI：
10.2337/figshare.13724113.v1
发表时间：
2021
期刊：
影响因子：
0
作者：
Ashcroft F
通讯作者：
Ashcroft F

Influences: Find a friend.

DOI：
10.1085/jgp.201812123
发表时间：
2018-07-02
期刊：
The Journal of general physiology
影响因子：
0
作者：
Ashcroft FM
通讯作者：
Ashcroft FM

Evaluating inositol phospholipid interactions with inward rectifier potassium channels and characterising their role in disease.

DOI：
10.1038/s42004-020-00391-0
发表时间：
2020-10-30
期刊：
COMMUNICATIONS CHEMISTRY
影响因子：
5.9
作者：
Pipatpolkai, Tanadet;Corey, Robin A.;Proks, Peter;Ashcroft, Frances M.;Stansfeld, Phillip J.
通讯作者：
Stansfeld, Phillip J.

Metabolic regulation of insulin secretion in health and disease

健康和疾病中胰岛素分泌的代谢调节