The role of SUR1 in synaptic and secretory vesicle function

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We're all familiar with the fact that machines are powered by electricity, but it's perhaps not so widely appreciated that the same is true for ourselves. Your ability to read and understand this page, to see and hear, to think and speak, and to move your arms and legs is due to the electrical events taking place in the nerve cells in your brain and the muscle cells in your limbs. And, in turn, that electrical activity is initiated and regulated by tiny protein pores embedded in the membranes of each one of your cells, known as ion channels.Nerve cells are used to transmit electrical signals round the body. Within our brains, billions of nerve cells also engage in a constant electrical conversation, directing all our thoughts and actions. But nerve cells are not physically connected to one another and the electrical impulse cannot jump the gap between them. Instead a chemical messenger, known as a neurotransmitter, is used to send signals from one cells to another. Transmission takes place at specialised junctions called synapses, where the two nerve cells come close together and the gap between them is very tiny. At the synapse, the tip of the nerve cell is densely packed with small membrane-bound vesicles filled with neurotransmitter, and when an electrical impulse arrives at the nerve terminal it causes the vesicles to release their contents into the gap between the two cells. The neurotransmitter then diffuses across the gap and stimulates an electrical impulse in the next cell. A similar process takes place in gland cells, which release hormones into the blood stream. This process also involves the packaging of the hormone into tiny vesicles which then fuse with the surface membrane of the cell and empty their contents into the bloodstream when the gland cell is stimulated. The hormones then travel around the body in the blood to their target organs. The way in which nerves work, how they talk to one another at synapses, and the role of ion channels in this process is explained in The Spark of Life, a book for the general reader written by one of the applicants of this grant (Frances Ashcroft). This project is focused on the precise way in which the release of vesicles from nerve endings and gland cells is controlled. We are particularly interested in an ion channel known as 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. It also is important in the nerve cells of the brain, and people with mutations in KATP channel genes not only get diabetes but may also have delayed development. Our preliminary data suggests that one of the proteins that makes up the KATP channel has a novel role in regulating vesicle function and release in both nerve and gland cells. Although we have known for some years that this protein (called SUR1) is present in the insulin secretory vesicles, we still don't fully understand what it does there. Recently, the mystery has deepened, as we discovered SUR1 is also present in vesicles at nerve endings in the brain. The aim of the grant is therefore to understand the role of SUR1 in both the synaptic and secretory vesicles. This question is of considerable scientific importance as it addresses a fundamental topic - how do cells communicate with one another? It is also of importance to the pharmaceutical industry because many clinically important drugs influence synaptic function and hormonal release. Elucidating the molecular pathways in which SUR1 is involved may lead to new targets for drug development. Finally, the methods that we propose to use are novel and will lead to the development of a new tool for scientists studying vesicle function. In addition, we are collaborating with a UK company to generate new applications for their microscopes.