The Structural Mechanism of K2P Channel Gating

几乎人体的每一个过程都在某种程度上受到电信号的控制，从我们的心脏跳动的方式，我们的肌肉运动的方式，到我们思考的方式。这些电信号由离子通道产生和控制，离子通道充当电“开关”，以控制带电离子如钾（K+）和钠（Na+）进出细胞的选择性运动。因此，它们在正常的细胞功能中起着至关重要的作用，并且已知它们的功能障碍会导致各种各样的疾病状态。“双孔”或“K2P”通道是在整个人体的许多不同组织中发现的钾通道的主要亚家族，并且参与许多重要的生理过程，特别是神经细胞中电活动的控制。然而，与许多其他类型的K+离子通道形成鲜明对比的是，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药物，这些药物可用作分子工具来探测K2P通道的结构及其打开和关闭的机制。我们还确定了两种特定的K2P通道（TREK和TRESK）之间的重要差异，这为我们提供了一个新的视角来了解这些通道的功能以及为什么它们的门控机制与其他类型的K+通道不同。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。与辉瑞的拟议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，这些工具，专业知识和资源通常在学术环境中无法获得，并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.