Functional dynamics of the KATP channel

离子通道对地球上的所有生命都是必不可少的。这些微小的门控孔位于我们每个细胞周围的膜上，它们的打开和关闭是我们一切行为的基础。你阅读这一页、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，从受孕到死亡，控制受精，控制我们的心跳，控制我们抵抗感染的能力，甚至控制我们的意识本身。许多药物和许多毒药通过调节这些微小分子机器的活动起作用，而离子通道功能受损是导致许多人类和动物疾病的原因。它们的重要功能作用在本书《生命的火花》中得到了解释，作者是该基金的申请者之一（Frances Ashcroft）。这个项目的重点是被称为KATP通道的离子通道。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。胰岛素是确保血糖水平不会升高过高的关键，而胰岛素不足会导致糖尿病。长期血糖升高对许多细胞有害，并引起肾病、眼病、心脏病和周围肢体感觉丧失（这往往导致无法识别的创伤，需要截肢）。因此，了解KATP通道功能具有高优先级。我们已经证明，当KATP通道的毛孔打开时，胰岛素不会被释放，当毛孔关闭时，胰岛素就会分泌。用于治疗2型糖尿病的葡萄糖和磺脲类药物都通过关闭通道刺激胰岛素释放。我们还发现，KATP通道基因的突变导致一种罕见的遗传性糖尿病（新生儿糖尿病或ND），出现在生命的前六个月内。突变的通道不再被葡萄糖正常关闭，从而影响胰岛素的释放。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向口服片剂治疗，其临床状况和生活质量得到了显著改善。目前拨款的目的之一是更精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-如核苷酸ATP和MgADP -如何与通道相互作用，影响其打开和关闭。我们也不完全了解有多少ND突变损害了这一过程。第二个目的是确定磺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关闭。这将有助于设计出新的、可能更好的治疗糖尿病的药物。为了实现这些目标，我们正在开发一种具有高空间和时间分辨率的新方法来研究配体（药物和核苷酸）与其受体的结合。这将为研究其他膜蛋白（如离子通道、转运体和受体）提供一种新的工具，其中许多膜蛋白会导致常见的人类疾病，如囊性纤维化，或者是主要的药物靶点。因此，我们的项目将具有重要的一般结果，以及特定于katp渠道的结果。

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.