ATP-SENSITIVE POTASSIUM CHANNELS AND INSULIN SECRETION

描述：胰腺ATP敏感性钾通道(KATP通道) 控制B细胞的胰岛素分泌。长期目标是了解如何 KATP通道在分子水平上被调节以控制胰岛素 分泌物。除了受细胞内ATP和ADP的调节外，a 属性，该属性使通道能够将细胞能量耦合到细胞 兴奋性，研究人员最近表明，该通道是深刻的 受膜磷脂调节。肌醇磷脂调节血管内皮细胞生长 KATP通道对ATP的敏感性超过几个数量级。这 调制提供了一种机制，允许通过生理方式选通通道 三磷酸腺苷和腺苷二磷酸浓度。相对于细胞内的调节 核苷酸，我们对肌醇磷脂调节通道的理解是 它还处于初级阶段。提出这项研究的目的是了解 这一新的调控机制的生理意义及其分子基础 机制。为了评估生理意义，调查人员将 控制胰岛素分泌细胞膜上的肌醇磷脂水平 以及-检查对通道活动和胰岛素分泌的影响。这个 研究人员还将破坏肌醇磷脂和肌醇之间的相互作用。 通过过度表达缺乏能力的突变通道在这些细胞中的通道 与肌醇磷脂相互作用，以及与之竞争的抑制性多肽 肌醇磷脂结合的内源性通道，并评价 生理结果。调查人员将确定结构元素 在参与肌醇磷脂调节的通道蛋白中使用 系统定点突变与电生理相结合的方法 监视通道和之间的功能交互的测量 磷脂酰肌醇，以及监测物理状态的生化测量 通道与肌醇磷脂之间的相互作用。我们提供的信息 建议获得对于理解KATP通道调节和， 因此，胰岛素的分泌。它将为新的治疗方法提供见解 胰岛素分泌疾病的治疗方法。

DESCRIPTION: The pancreatic ATP-sensitive potassium channels (KATP channels) control insulin secretion in B-cells. The long-term goal is to understand how KATP channels are regulated at the molecular level to control insulin secretion. In addition to being regulated by intracellular ATP and ADP, a property, which enables the channel to couple, cell energy to cell excitability, the investigators recently showed that the channel is profoundly regulated by membrane phosphoinositides. Phosphoinositides modulate the sensitivity of KATP channels to ATP over several orders of magnitude. This modulation provides a mechanism to allow channels to be gated by physiological concentrations of ATP and ADP. Relative to regulation by intracellular nucleotides, our understanding of channel regulation by phosphoinositides is still in its infancy. The research proposed is aimed at understanding the physiological significance and the molecular basis of this novel regulatory mechanism. To assess the physiological significance, the investigators will manipulate membrane phosphoinositide levels in insulin-secreting cells and-examine the effects on channel activity and insulin secretion. The investigators will also disrupt the interaction between phosphoinositides and channels in these cells by overexpressing mutant channels lacking the ability to interact with phosphoinositides, and inhibitory peptides that compete with endogenous channels for phosphoinositide binding, and evaluate the physiological outcome. The investigators will determine the structural elements within the channel proteins involved in phosphoinositide regulation using systematic site-directed mutagenesis approach combined with electrophysiolgical measurements that monitor functional interaction between the channel and phosphoinositides, and with biochemical measurements that monitor the physical interaction between the channel and phosphoinositides. The information we propose to obtain is crucial for understanding KATP channel regulation and, hence, insulin secretion. It will provide insights to novel therapeutic approaches to diseases of insulin secretion.