The Structural Mechanism of K2P Channel Gating

从我们的心脏跳动的方式，肌肉的运动方式，到我们的思维方式，人体几乎每一个单独的过程都在一定程度上受到电信号的控制。这些电信号是由离子通道产生和控制的，离子通道充当电气“开关”，控制钾(K+)和钠(Na+)等带电离子有选择地进出细胞。因此，它们在正常的细胞功能中起着根本性的重要作用，它们的功能障碍被认为会导致多种疾病状态。“双孔”或“K2P”通道是钾通道的一个主要亚家族，存在于人体许多不同的组织中，参与许多重要的生理过程，特别是神经细胞中的电活动的控制。然而，与许多其他类型的K+离子通道相比，控制K2P通道功能的分子机制及其3D结构仍然知之甚少。为了解决这个问题，我们最近发现了一系列高亲和力的药物，可以作为分子工具来探索K2P通道的结构和打开和关闭的机制。我们还发现了两个特殊的K2P通道(Trek和Tresk)之间的一个重要差异，这为我们提供了一个新的视角，了解这些通道是如何发挥作用的，以及为什么它们的门控机制不同于其他类型的K+通道。在拟议的研究中，我们的目标是利用这些令人兴奋的新发现，并使用这些分子工具来研究K2P通道门控的结构机制。与辉瑞拟议的工业合作伙伴关系还为我们提供了获得各种化学工具、专业知识和资源的途径，这些工具、专业知识和资源通常是学术环境中无法获得的，这使我们处于能够实现这些目标的独特地位。

Almost every single process in the human body is controlled at some level by electrical signals, from the way our hearts beat, the way our muscles move, to the way we think. These electrical signals are generated and controlled by ion channels which act as electrical 'switches' to control the selective movement of charged ions like potassium (K+) and sodium (Na+) into and out of the cell. They therefore play a fundamentally important role in normal cellular function and their dysfunction is known to result in a wide variety of disease states. The 'Two-Pore' or 'K2P' channels are a major subfamily of potassium channels found in many different tissues throughout the human body and are involved in many important physiological processes, in particular the control of electrical activity in nerve cells. However, in marked contrast to many other types of K+ ion channel, the molecular mechanisms which control K2P channel function and their 3D structure are still poorly understood. In an attempt to tackle this problem we have recently identified a range of high-affinity drugs which can be used as molecular tools to probe the structure of the K2P channel and the mechanisms by which they open and close. We have also identified an important difference between two particular K2P channels (TREK and TRESK) which now provides us with a fresh insight into how these channels function and why their gating mechanism is different to other types of K+ channel. In the proposed study we aim to exploit these exciting new findings and to use these molecular tools to investigate the structural mechanism of K2P channel gating. The proposed industrial partnership with Pfizer also provides us with access to a variety of chemical tools, expertise and resources that are not normally available in an academic environment and which place us in a unique position to be able to pursue these goals.