Understanding the Molecular Mechanisms of Gating in TREK K2P K+ Channels

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Our ability to sense changes in pressure and temperature, as well as our ability to detect a wide variety of chemical agents, is not only essential for normal bodily function, but also for the perception of pain. Understanding the molecular mechanisms which control these processes represents one of the most important goals in sensory biology.When our body comes into contact with potentially dangerous stimuli a complex series of events initiates innate protective mechanisms designed to minimize or avoid injury. For example, extreme temperatures, mechanical stress, and chemical irritants such as acid are detected by specialised receptors clustered at the ends of sensory nerve fibres which convert these stimuli into electrical signals. These signals are then rapidly transmitted from distant sites in the body to the spinal cord and to higher processing centres in the brain which interpret these signals to initiate an appropriate response.These electrical signals are orchestrated by distinct groups of cell membrane proteins known as 'ion channels' of which there are many hundreds of different kinds in the human body. However, there is now significant evidence that one particular group known as the 'two-pore' or 'K2P' family of potassium selective channels play an important role at many different stages of this pathway, including the specific detection of both normal and painful stimuli.Although the sensation of pain is generally beneficial for the avoidance of greater overall tissue damage, unwanted pain confers a substantial burden on individuals, employers, healthcare systems and society in general. Indeed, the personal and socioeconomic impact of chronic pain is as great as, or greater, than that of other established healthcare priorities. There is therefore a tremendous need for better and more effective drugs for the treatment of pain and K2P channels represent attractive therapeutic targets for such drugs.In a major recent advance, we have now determined the 3D structures of two human K2P channels (TREK-1 and TREK-2) using X-ray crystallography. We were also able to determine their structures in different conformational states which has provided new insights into how these channels open and close to 'switch' electrical signals on and off.More importantly, we were also able to solve the structure of TREK-2 in complex with an inhibitor, fluoxetine (Prozac). Although not the principal target of this drug, identification of the binding site has provided an important insight into the biophysical mechanisms of TREK-2 channel gating and regulation by small molecules, as well as some of the potential off-target effects of this commonly prescribed drug.In this research project we aim to exploit these exciting new findings to define a structural basis for how K2P channels open and close to control electrical signals, and also to understand how other small molecules and physiologically relevant regulatory pathways control this process.The proposed industrial partnership with Pfizer Neusentis also provides us with access to a variety of chemical tools, expertise and resources not normally available in a standard academic environment, and therefore places us in a unique position to be able to pursue these goals.