The Structural and Functional Basis of Defective X-Gating in a Novel TASK-1 Channelopathy Associated with Sleep Apnea

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A UK-led study recently identified 28 novel genes with a high burden of de novo mutations associated with developmental disorders (Kaplanis et al, Nature, 2020). In collaboration with this group, we have exciting new evidence that a specific group of these patients, who also suffer sleep apnea, all have mutations in KCNK3 which encodes TASK-1. We have named this novel channelopathy as "Developmental Delay with Sleep Apnea" (DDSA).Sleep apnea is a common disorder affecting hundreds of millions of people worldwide and is a major public health burden with a significant economic impact. Consequently, there is an unmet clinical need for more effective treatments, but the underlying molecular mechanisms involved are often unclear.TASK1 channels have previously been implicated in sleep apnea, and drugs which inhibit TASK-1 are in clinical trials for its treatment. However, until now, mutations in KCNK3 were currently linked to a very different disorder - Primary Pulmonary Hypertension - and so the mechanistic link between TASK-1 and sleep apnea was not fully understood.We now show that, unlike the loss-of-function mutations found in PAH, these new DDSA mutations cluster near the 'X-gate', a novel structural gating motif we recently identified in a closed-state crystal structure of TASK-1 (Rödström et al, Nature, 2020). These mutants all produce a marked gain-of-function in channel activity. Importantly, they also render TASK-1 insensitive to GPCR-mediated inhibition thereby amplifying the gain-of-function effect, and we show these defects arise from dysfunctional X-gating. Fortunately, we also discovered that many TASK-1 inhibitors, including those currently in clinical trials, still inhibit the mutant channels thereby offering possible therapeutic strategies for these patients and those with sleep apnea.It is currently unclear how GPCR pathways regulate TASK-1 channel activity. It is also unknown how theX-gate opens/closes to control permeation, or how channel activity is regulated by these clinically-relevant inhibitors. A series of fundamental studies of TASK-1 channel structure, function and pharmacology are therefore needed to address this deficit.Based on these findings, and a range of new experimental tools we also have available, this project aimsto address fundamentally important questions which fall squarely within the BBSRC remit of world-leading basic bioscience for an integrated understanding of health:-How does the TASK-1 channel open and close, and how is it regulated by natural ligands?- How do novel small molecule activators and inhibitors regulate channel gating?- How is X-gating normally regulated, and how does this become defective in the disease state?Overall this project will generate a step change in our understanding of TASK-1 channels and their mechanism of regulation by GPCR coupled pathways in both health and disease. It will also address the molecular mechanism of action of new drugs being developed to target these channels.