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Functional dynamics of the KATP channel

KATP 通道的功能动力学

基本信息

批准号：
BB/R002517/1
负责人：
Frances Ashcroft
金额：
$ 56.55万
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%2FR002517%2F1
关键词：
Functional dynamics KATP channel

项目摘要

Ion channels are essential for all life on Earth. These tiny gated pores sit in the membrane which surrounds every one of our cells, and their opening and closing underlies everything that we do. Your ability to read this page, to move your limbs, to think and speak is down to the activity of ion channels. They govern every aspect of our lives, from conception to the grave, controlling fertilization, the beating of our hearts, our ability to fight infection, even consciousness itself. A multitude of medicinal drugs and many poisons work by regulating the activity of these minute molecular machines, and impaired ion channel function is responsible for many human and animal diseases. Their important functional roles are explained in the book 'The Spark of Life' by one of the applicants of this grant (Frances Ashcroft). This project is focused on an ion channel known as the 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. Insulin is essential for ensuring blood glucose levels do not rise too high and an insufficiency of insulin results in diabetes. Chronic elevation of blood glucose is deleterious to many cells, and gives rise to kidney disease, eye disease, heart disease and loss of sensation in the peripheral limbs (which often leads to unrecognized trauma, necessitating amputation). Understanding KATP channel function is therefore of high priority. We have shown that when the KATP channel is pore is open, insulin is not released and when the pore is shut insulin is secreted. Both glucose and the sulphonylurea drugs used to treat type 2 diabetes stimulate insulin release by closing the channel. We have also shown that mutations in KATP channel genes cause a rare inherited form of diabetes (neonatal diabetes or ND), which presents within the first six months of life. The mutant channels are no longer closed properly by glucose, impairing insulin release. However, sulphonylurea drugs are still effective. This finding has enabled most ND patients to switch from insulin injections to oral tablet therapy, with considerable improvement in their clinical condition and quality of life. One aim of the current grant is to understand more precisely how glucose closes the KATP channel. We know this requires breakdown (metabolism) of the sugar but we still don't fully understand how metabolites - such as the nucleotides ATP and MgADP - interact with the channel to influence its opening and closing. Nor do we fully understand how many of the ND mutations impair this process. A second aim is to identify the binding site for sulphonylurea drugs on the channel, and determine how drug binding promotes channel closure. This should facilitate the design of new and potentially better drugs to treat diabetes. To address these aims, we are developing a novel approach to studying the binding of ligands (drugs and nucleotides) to their receptors that has high spatial and temporal resolution. This should result in a new tool for studying other membrane proteins (such as ion channels, transporters and receptors) many of which cause common human diseases, such as cystic fibrosis, or are major drug targets. Thus our project will have important general, as well as KATP-channel-specific, outcomes.

离子通道对于地球上的所有生命都至关重要。这些微小的门控孔位于包围我们每个细胞的膜中，它们的打开和关闭是我们所做的一切的基础。您阅读本页、移动四肢、思考和说话的能力都取决于离子通道的活动。它们控制着我们生活的方方面面，从受孕到坟墓，控制受精、心脏跳动、抵抗感染的能力，甚至意识本身。许多药物和许多毒物通过调节这些微小分子机器的活性来发挥作用，离子通道功能受损是许多人类和动物疾病的原因。此项资助的申请人之一（弗朗西斯·阿什克罗夫特）在《生命的火花》一书中解释了它们的重要功能作用。该项目的重点是称为 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，因为它控制胰腺β细胞释放胰岛素。胰岛素对于确保血糖水平不升得太高至关重要，胰岛素不足会导致糖尿病。血糖慢性升高对许多细胞有害，并导致肾病、眼病、心脏病和周围肢体感觉丧失（这通常会导致无法识别的创伤，需要截肢）。因此，了解 KATP 通道功能至关重要。我们已经证明，当 KATP 通道孔打开时，胰岛素不会释放，而当孔关闭时，胰岛素就会分泌。葡萄糖和用于治疗 2 型糖尿病的磺酰脲类药物均通过关闭通道来刺激胰岛素释放。我们还表明，KATP 通道基因的突变会导致一种罕见的遗传性糖尿病（新生儿糖尿病或 ND），这种疾病会在生命的前六个月内出现。突变通道不再被葡萄糖正确关闭，从而损害胰岛素释放。然而，磺脲类药物仍然有效。这一发现使大多数ND患者从胰岛素注射转为口服片剂治疗，其临床状况和生活质量得到了显着改善。当前资助的目的之一是更准确地了解葡萄糖如何关闭 KATP 通道。我们知道这需要糖的分解（代谢），但我们仍然不完全了解代谢物（例如核苷酸 ATP 和 MgADP）如何与通道相互作用以影响其打开和关闭。我们也不完全了解有多少 ND 突变会损害这一过程。第二个目标是确定磺酰脲类药物在通道上的结合位点，并确定药物结合如何促进通道闭合。这应该有助于设计新的、可能更好的治疗糖尿病的药物。为了实现这些目标，我们正在开发一种新方法来研究配体（药物和核苷酸）与其受体的结合，该方法具有高空间和时间分辨率。这应该会产生一种新的工具来研究其他膜蛋白（例如离子通道、转运蛋白和受体），其中许多膜蛋白会引起常见的人类疾病，例如囊性纤维化，或者是主要的药物靶标。因此，我们的项目将具有重要的一般成果以及 KATP 渠道特定成果。

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）

Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.

DOI：
10.1021/acs.jctc.1c00547
发表时间：
2021-10-12
期刊：
Journal of chemical theory and computation
影响因子：
5.5
作者：
Ansell TB;Curran L;Horrell MR;Pipatpolkai T;Letham SC;Song W;Siebold C;Stansfeld PJ;Sansom MSP;Corey RA
通讯作者：
Corey RA

Structural basis of lipopolysaccharide maturation by the O-antigen ligase.