The role of NAADP and the two-pore channel proteins in mediating insulin secretion in pancreatic beta cells

NAADP 和二孔通道蛋白在介导胰腺 β 细胞胰岛素分泌中的作用

• 批准号: G0901521/1
• 负责人: A Galione
• 金额: $ 190.18万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0901521%2F1
• 关键词: role; NAADP; two; pore; channel

Glucose is an important fuel for the cells of our bodies, allowing them to carry out their many functions. After a meal, glucose passes from our gut into the blood where it is carried to the pancreas. A set of specialized cells called pancreatic beta-cells respond to the increase of glucose levels in the blood by releasing the hormone insulin. Insulin is then carried by the blood to the organs of the body where it binds to a specific protein or receptor on the surface of cells and triggers a cascade of chemical events inside each cell to promote glucose transport into the cell for use as a fuel or for storage. How glucose stimulates insulin release is a key question, since a defect in this mechanism is responsible for type 2 diabetes. Diabetes is associated with decreased glucose uptake into cells, and chronically high levels of glucose in the blood, leading to multiple pathological events. One set of key proteins in the membranes surrounding beta-cells are called potassium channels. These close in response to uptake and metabolism of glucose, and also after treatment with some anti-diabetic drugs, leading to electrical changes resulting in an increase of calcium ions inside the beta-cell. Calcium ions act as a signal to promote release of insulin from storage granules from inside the cells into the blood. However, there is now evidence that glucose may also trigger insulin release by mechanisms independent of these potassium channels. Our preliminary work has shown that an important additional mechanism may involve a molecule called NAADP, which is generated inside the beta-cell in response to raised glucose levels and then releases calcium from internal stores within the cell to promote insulin release. Recently we made a major step forward by identifying the target receptor for NAADP in the cell as being the two-pore channel (TPC) proteins. We propose to study how production of NAADP is controlled in beta-cells and discover the precise way in which it acts upon the TPCs and other connected signalling proteins to stimulate release of insulin. Our work should thus uncover new molecular components involved in insulin release which may be impaired in diabetes and may represent new targets for drugs in the treatment of this disease.

葡萄糖是我们身体细胞的重要燃料，使它们能够执行许多功能。饭后，葡萄糖从我们的肠道进入血液，在那里它被带到胰腺。一组称为胰腺β细胞的专门细胞通过释放激素胰岛素来响应血液中葡萄糖水平的增加。然后，胰岛素被血液运送到身体的器官，在那里它与细胞表面上的特定蛋白质或受体结合，并在每个细胞内触发一系列化学事件，以促进葡萄糖转运到细胞中，用作燃料或储存。葡萄糖如何刺激胰岛素释放是一个关键问题，因为这种机制的缺陷是2型糖尿病的原因。糖尿病与细胞对葡萄糖的吸收减少以及血液中葡萄糖水平长期居高不下有关，从而导致多种病理事件。在β细胞周围的膜中有一组关键蛋白质被称为钾通道。这些关闭响应于葡萄糖的摄取和代谢，并且在用一些抗糖尿病药物治疗后，导致电变化，导致β细胞内钙离子的增加。钙离子作为一种信号，促进胰岛素从细胞内的储存颗粒释放到血液中。然而，现在有证据表明，葡萄糖也可能通过独立于这些钾通道的机制触发胰岛素释放。我们的初步工作表明，一个重要的额外机制可能涉及一种名为NAADP的分子，该分子在β细胞内响应于葡萄糖水平升高而产生，然后从细胞内的内部储存中释放钙以促进胰岛素释放。最近，我们通过鉴定细胞中NAADP的靶受体作为双孔通道（TPC）蛋白质向前迈出了重要一步。我们建议研究β细胞中NAADP的产生是如何控制的，并发现它作用于TPC和其他相关信号蛋白以刺激胰岛素释放的精确方式。因此，我们的工作应该发现新的分子成分参与胰岛素的释放，这可能是受损的糖尿病，并可能代表新的目标药物治疗这种疾病。