ATP-sensitive potassium channels and insulin secretion

ATP敏感钾通道和胰岛素分泌

• 批准号: 7017115
• 负责人: Show-Ling Shyng
• 金额: $ 27.28万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017115
• 关键词: SDS polyacrylamide gel electrophoresis; adenosine diphosphate; adenosine triphosphate; binding proteins; binding sites; cell membrane; electron microscopy; electrophysiology; immunoelectron microscopy; insulin; laboratory mouse; laboratory rat; membrane activity; pancreatic islet function; phosphatidylinositols; potassium channel; protein kinase C; protein protein interaction; protein structure function; recombinant proteins; site directed mutagenesis; sulfonylurea; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): ATP-sensitive potassium (K-ATP) channels in pancreatic beta-cells couple blood glucose levels to membrane excitability to control insulin secretion. Loss-of-function K-ATP channel mutations cause congenital hyperinsulinism, whereas gain-of-function mutations increase the risk of diabetes. Our long-term goal is to understand how regulation of K-ATP channels in pancreatic beta-cells affects insulin secretion in health and disease. To fulfill their functional role, K-ATP channels not only need to have the exquisite electrophysiological properties but also need to be delivered to the right place at the right time in order to interact with the various signaling molecules. The work conducted during the previous award period found that defective K-ATP channel trafficking that results in reduced surface channel expression is a major mechanism underlying congenital hyperinsulinism. Genetic or pharmacological manipulations that correct channel trafficking defects restore the function of some mutant channels. Our findings underscore the importance of trafficking regulation of K-ATP channels in beta-cell function. In this proposal, we aim to elucidate the trafficking pathway of K-ATP channels in beta-cells, and to study how channel trafficking is affected by disease mutations and by physiological and pharmacological stimuli. The goals of the proposed studies are: (1) to delineate the trafficking itinerary of K-ATP channels in beta-cells by determining whether channels are sorted into insulin granules prior to insertion into the plasma membrane, whether surface channels are associated with lipid rafts, and whether internalized channels are recycled; (2) to study how disease mutations affect the trafficking of K-ATP channels, and how channel trafficking defects can be corrected; (3) to investigate how physiological and pharmacological stimuli, specifically, protein kinase C activation and sulfonylurea treatments, affect K-ATP channel trafficking in beta-cells. We will use a combination of molecular, biochemical, cell biological, and electrophysiological approach to address these issues. These studies will better our understanding of the trafficking regulation of K-ATP channels in beta-cells to allow for an integrated view of the spatial and temporal control of K-ATP channel signaling, and may lead to novel therapeutic strategies for insulin secretion diseases.

描述（由申请人提供）：胰腺β-细胞中的ATP敏感钾（K-ATP）通道情侣血糖水平，以控制胰岛素分泌的膜兴奋性。功能丧失的K-ATP通道突变会导致先天性高胰岛素主义，而功能收益突变会增加糖尿病的风险。我们的长期目标是了解胰腺β细胞中K-ATP通道的调节如何影响健康和疾病中的胰岛素分泌。为了履行其功能作用，K-ATP通道不仅需要具有精美的电生理特性，而且还需要在正确的时间传递到正确的位置，以便与各种信号分子相互作用。在上一个奖项期间进行的工作发现，有缺陷的K-ATP渠道运输导致表面渠道表达降低是先天性高胰岛素异常的主要机制。纠正通道运输缺陷的遗传或药理操作会恢复某些突变通道的功能。我们的发现强调了K-ATP通道在β细胞函数中进行运输调节的重要性。在此提案中，我们旨在阐明β细胞中K-ATP通道的运输途径，并研究如何受疾病突变以及生理和药理刺激的影响。拟议的研究的目标是：（1）通过确定是否将通道在插入质膜中的胰岛素颗粒中分类为胰岛素颗粒，以描绘β细胞中K-ATP通道的运输行程，以及表面通道是否与脂质筏相关，以及是否与内部频道相关联。 （2）研究疾病突变如何影响K-ATP通道的运输，以及如何纠正通道贩运缺陷； （3）研究生理和药理刺激，特别是蛋白激酶C活化和磺酰尿素处理如何影响β细胞中的K-ATP通道运输。我们将结合分子，生化，细胞生物学和电生理方法来解决这些问题。这些研究将更好地理解Beta细胞中K-ATP通道的运输调节，以允许对K-ATP通道信号的空间和时间控制的综合观点，并可能导致胰岛素分泌疾病的新型治疗策略。