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

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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.