ATP-sensitive potassium channels and insulin secretion

描述（由申请人提供）：胰腺b细胞中的atp敏感钾（KATP）通道将血糖浓度与膜兴奋性偶联，从而控制胰岛素分泌。b细胞KATP通道是由4个磺酰脲受体1和4个向内整流钾通道Kir6.2亚基组成的复合物。导致通道功能丧失的通道基因突变已经被认为是胰岛素分泌疾病先天性高胰岛素症的基础。最近，功能获得通道突变被发现是新生儿糖尿病的主要原因。我们研究的长期目标是了解b细胞KATP通道的调节，这种调节是如何被通道突变干扰而导致疾病的，以及我们如何操纵通道调节来对抗胰岛素分泌疾病。迄今为止，该基金支持的工作已经确定了几种通道突变导致胰岛素分泌异常的新机制。其中，导致表面通道表达水平降低的缺陷通道生物发生和运输在先天性高胰岛素血症相关突变中最为普遍。有趣的是，我们最近的工作发现许多新生儿糖尿病突变也影响通道的生物发生和表面表达。重要的是，我们已经确定了一组突变，其运输缺陷可以通过磺脲类药物（通常用于治疗II型糖尿病的药物）在药理学上得到纠正。这些发现强调了通道生物发生和运输的重要性，这反过来控制表面通道表达，在b细胞功能和操纵这些细胞事件治疗胰岛素分泌疾病的潜力。在这项更新申请中，我们将以这些发现为基础，进一步研究b细胞中KATP通道的生物发生和运输调节。结合分子、生化、细胞生物学和电生理学方法，我们将(1)描述b细胞中KATP通道的生物发生和运输途径，(2)确定通道突变如何改变通道表达和门控，从而导致b细胞功能障碍和疾病。(3)阐明磺脲类药物修复通道生物发生/运输缺陷的机制，并评估磺脲类药物在恢复b细胞突变通道表达和功能方面的作用。提出的研究将更好地理解KATP通道运输的调节如何促进胰岛素分泌的调节。这些信息对于我们整合KATP通道调节的所有方面以充分了解这些通道在生理和病理条件下在b细胞功能中的作用的长期目标至关重要。公共卫生相关性：胰岛素分泌异常可导致危及生命的疾病，如糖尿病和高胰岛素血症。我们建议研究KATP通道（参与胰岛素分泌调节的关键分子）的突变如何影响通道特性从而导致疾病，以及我们如何纠正由突变引起的通道缺陷。这些研究与人类健康高度相关，并可能为这些毁灭性疾病带来新的治疗策略。

DESCRIPTION (provided by applicant): ATP-sensitive potassium (KATP) channels in pancreatic b-cells couple blood glucose concentrations to membrane excitability thus control insulin secretion. The b-cell KATP channel is a complex of four sulfonylurea receptor 1 and four inwardly rectifying potassium channel Kir6.2 subunits. Mutations in the channel genes that lead to loss of channel function have been known for quite some time to underlie the insulin secretion disease congenital hyperinsulinism. More recently, gain-of-function channel mutations have been discovered as a major cause of neonatal diabetes. The long-term goal of our research is to understand regulation of b-cell KATP channels, how this regulation is perturbed by channel mutations to cause disease and how we may manipulate channel regulation to combat insulin secretion disease. Work supported by this grant to date has identified several novel mechanisms by which channel mutations cause abnormal insulin secretion. Among these, defective channel biogenesis and trafficking that results in reduced surface channel expression levels is the most prevalent in mutations associated with congenital hyperinsulinism. Interestingly, our recent work found many neonatal diabetes mutations also affect channel biogenesis and surface expression. Of significance, we have identified a group of mutations whose trafficking defects could be corrected pharmacologically by sulfonylureas, drugs commonly used to treat type II diabetes. These findings underscore the importance of channel biogenesis and trafficking, which in turn control surface channel expression, in b-cell function and the potential of manipulating these cellular events to treat insulin secretion disease. In this renewal application, we will build up on these findings and further investigate the biogenesis and trafficking regulation of KATP channels in b-cells. Using a combination of molecular, biochemical, cell biological and electrophysiological approaches we will (1) delineate the biogenesis and trafficking pathways of KATP channels in b-cells, (2) determine how channel mutations alter channel expression and gating to cause b-cell dysfunction and disease, and (3) elucidate the mechanism by which sulfonylureas rescue channel biogenesis/trafficking defects and assess the utility of sulfonylureas in restoring mutant channel expression and function in b-cells. The proposed studies will better our understanding of how regulation of KATP channel trafficking contributes to regulation of insulin secretion. This information is critical for our long-term goal of integrating all aspects of KATP channel regulation to fully understand the role of these channels in b-cell function under physiological and pathological conditions. PUBLIC HEALTH RELEVANCE: Abnormal insulin secretion results in life-threatening diseases such as diabetes and hyperinsulinism. We propose to study how mutations in the KATP channel, a key molecule involved in regulation of insulin secretion, affect channel properties to cause disease and how we can correct channel defects caused by mutations. These studies are highly relevant to human health and may lead to novel therapeutic strategies for these devastating diseases.