The structural and functional basis of defective TASK1 X-Gating in a novel channelopathy associated with sleep apnoea

离子通道在几乎每个人体细胞中都能产生电流，并且是细胞健康运作所必需的。它们的特性可以通过许多不同的信号通路调节，它们代表了治疗许多不同疾病的重要治疗靶点。睡眠呼吸暂停是一种常见的疾病，影响着全球近七分之一的人。这些患者在睡眠时不能正常呼吸，并因此受到睡眠中断的困扰，这不仅给公共卫生造成了重大负担，而且还降低了他们的生活质量，增加了患其他严重疾病的风险。因此，需要更有效的药物来治疗这一问题，但这种复杂疾病的分子机制尚不清楚。在最近的一项研究中，临床同事在患有发育迟缓的儿童身上发现了一种基因的新突变，这些儿童也患有睡眠呼吸暂停症。该基因（KCNK3）编码钾离子通道TASK1，是钾离子通道“K2P”家族的一员。我们的实验室研究了这些通道的功能特性，我们最近也用x射线晶体学确定了TASK1通道的三维结构。针对TASK1的药物目前正在临床试验中，用于治疗睡眠呼吸暂停，但其与睡眠呼吸暂停之间的联系机制尚不清楚，尤其是因为已知TASK1的突变会导致一种完全不同的疾病，一种肺高压（PPH4）。因此，我们研究了这些突变，发现与导致PPH4的“功能丧失”突变不同，TASK1中这些新的“睡眠呼吸暂停”突变都会导致通道过度活跃的“功能获得”。我们还表明，突变都位于通道的“x门”区域内或附近，该区域充当打开和关闭通道的“开关”。此外，我们还兴奋地发现，这些突变还可以防止通道被一类重要的被称为gpcr的信号受体关闭。这意味着当正常的TASK1通道的活动被这些信号关闭时，这些突变通道的活动仍然非常高，因此使问题更加严重。幸运的是，我们发现了几种药物，包括目前用于治疗睡眠呼吸暂停的药物，可以抑制这些过度活跃的突变通道，从而为这些儿童提供了可能的治疗希望。在本研究中，我们的目标是研究突变通道的结构特性及其传导的电流。这将帮助我们解决一些重要的问题，例如：TASK1中的“x门”是如何打开和关闭的？它是如何被我们现有的新药或自然信号通路（例如GPCRs）调节的？在疾病状态下，这一切是如何出错的？这些答案将为我们理解TASK1通道及其在疾病中的功能障碍提供重大进展。它还将有助于为当前和未来治疗睡眠呼吸暂停的策略设计提供信息。

Ion channels contribute to the electrical currents found in nearly every human cell and are required for their healthy function. Their properties can be regulated by many different signalling pathways, and they represent important therapeutic targets for treatment of many different diseases.Sleep apnea is a common disorder that affects almost 1 in 7 people worldwide. The failure of these patients to breathe properly when asleep, and the interrupted sleep they suffer as a result, not only imposes a major public health burden, but also decreases their quality of life and increases the risk of other serious diseases. Consequently, more effective drugs are needed to treat this problem but the molecular mechanisms involved in this complex disease are unclear.In a recent study, clinical colleagues identified new mutations in a gene found in children with developmental delay who are unique in also suffering from sleep apnea. The gene involved (KCNK3) encodes the TASK1 potassium ion channel, a member of the "K2P" family of potassium channels. Our laboratory studies the functional properties of these channels and we have also recently determined the 3-Dimensional structure of the TASK1 channel using X-ray crystallography.Drugs which target TASK1 are currently in clinical trials for the treatment of sleep apnea, but the mechanisms which link it with sleep apnea are poorly understood, not least because mutations in TASK1 are known to cause a completely different disease, a form of pulmonary hypertension (PPH4).We therefore investigated these mutations and found that, unlike the 'loss-of-function' mutations which cause PPH4, these new 'sleep apnea' mutations in TASK1 all cause a 'gain-of-function' where the channels become overactive. We also show that the mutations are all located in/near a region of the channel known as the 'X-gate' which acts as the 'switch' to turn the channel on and off. In addition we were excited to find that these mutations also prevent the channel from being turned off by an important class of signal receptors known as GPCRs. This means that when the activity of normal TASK1 channels has been turned off by these signals, the activity of these mutant channel still remains very high and so makes the problem even worse. Fortunately, we show that several drugs, including those currently being tested for the treatment of sleep apnea can inhibit these overactive, mutant channels thereby offering hope of possible treatment for these children.In the proposed study we aim to investigate the structural properties of the mutant channels and the electrical currents they conduct. This will help us to address important questions such as: How does the 'X-gate' in TASK1 open and close? How is it regulated by the new drugs we have available or by natural signalling pathways (e.g. GPCRs), and how does this all go wrong in the disease state?The answers will provide a major advance in our understanding of TASK1 channels and their dysfunction in disease. It will also help inform the design of both current and future strategies to treat sleep apnea.