Functional dynamics of the KATP channel

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Ion channels are essential for all life on Earth. These tiny gated pores sit in the membrane which surrounds every one of our cells, and their opening and closing underlies everything that we do. Your ability to read this page, to move your limbs, to think and speak is down to the activity of ion channels. They govern every aspect of our lives, from conception to the grave, controlling fertilization, the beating of our hearts, our ability to fight infection, even consciousness itself. A multitude of medicinal drugs and many poisons work by regulating the activity of these minute molecular machines, and impaired ion channel function is responsible for many human and animal diseases. Their important functional roles are explained in the book 'The Spark of Life' by one of the applicants of this grant (Frances Ashcroft). This project is focused on an ion channel known as the KATP channel. It plays a very important role in the regulation of blood glucose levels because it controls the release of the hormone insulin from the beta-cells of the pancreas. Insulin is essential for ensuring blood glucose levels do not rise too high and an insufficiency of insulin results in diabetes. Chronic elevation of blood glucose is deleterious to many cells, and gives rise to kidney disease, eye disease, heart disease and loss of sensation in the peripheral limbs (which often leads to unrecognized trauma, necessitating amputation). Understanding KATP channel function is therefore of high priority. We have shown that when the KATP channel is pore is open, insulin is not released and when the pore is shut insulin is secreted. Both glucose and the sulphonylurea drugs used to treat type 2 diabetes stimulate insulin release by closing the channel. We have also shown that mutations in KATP channel genes cause a rare inherited form of diabetes (neonatal diabetes or ND), which presents within the first six months of life. The mutant channels are no longer closed properly by glucose, impairing insulin release. However, sulphonylurea drugs are still effective. This finding has enabled most ND patients to switch from insulin injections to oral tablet therapy, with considerable improvement in their clinical condition and quality of life. One aim of the current grant is to understand more precisely how glucose closes the KATP channel. We know this requires breakdown (metabolism) of the sugar but we still don't fully understand how metabolites - such as the nucleotides ATP and MgADP - interact with the channel to influence its opening and closing. Nor do we fully understand how many of the ND mutations impair this process. A second aim is to identify the binding site for sulphonylurea drugs on the channel, and determine how drug binding promotes channel closure. This should facilitate the design of new and potentially better drugs to treat diabetes. To address these aims, we are developing a novel approach to studying the binding of ligands (drugs and nucleotides) to their receptors that has high spatial and temporal resolution. This should result in a new tool for studying other membrane proteins (such as ion channels, transporters and receptors) many of which cause common human diseases, such as cystic fibrosis, or are major drug targets. Thus our project will have important general, as well as KATP-channel-specific, outcomes.