K+ Channel Expression in Pancreatic Beta-Cells

胰腺 β 细胞中 K 通道的表达

• 批准号: 8006768
• 负责人: Louis H. Philipson
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-04 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8006768
• 关键词: Ablation; Action Potentials; Address; Affect; Agonist; Calcium Signaling; Calcium-Activated Potassium Channel; Cell membrane; Cells; Computer Simulation; Coupling; Cyclic AMP-Dependent Protein Kinases; Data; Diabetes Mellitus; Dominant-Negative Mutation; Electric Capacitance; Exhibits; Fatty acid glycerol esters; Generations; Glucose; Health; Human; Hypoglycemia; Insulin Resistance; Islets of Langerhans; Knock-out; Kv2.1 channel; Measurement; Measures; Mediating; Membrane; Membrane Potentials; Metabolism; Modeling; Molecular; Molecular Target; Movement; Mus; Pathogenesis; Phosphorylation; Physiological; Play; Potassium Channel; Production; Property; Publishing; Regulation; Relative (related person); Rest; Rodent; Role; Structure of beta Cell of islet; Testing; Tetraethylammonium; arachidonate; base; blood glucose regulation; channel blockers; diabetic; feeding; imaging modality; insulin granule; insulin secretion; islet; mathematical model; mouse model; novel; potassium ion; public health relevance; response; voltage

DESCRIPTION (provided by applicant): The overall objective of this revised proposal is to elucidate the molecular mechanisms coupling electrical excitability of ¿-cells to glucose-induced insulin secretion (GSIS) in normal and diabetic states. We seek to test hypotheses concerning the role of voltage- dependent K+ (Kv) channels in regulating electrical activity and changes in intracellular free Ca2+ concentration ([Ca2+]i) that triggers GSIS. Once metabolism leads to closure of KATP channels generating action potentials (APs), Kv channels serve a distinct role in repolarizing the ¿-cell membrane, resulting in Ca2+ transients necessary for insulin secretion. Incretin agonists used to treat diabetes reduce Kv currents by a PKA- dependent mechanism, but the identity of the Kv channels involved remains undefined. The Kv channel Kv2.1 is the predominant Kv channel in ¿-cells, thought to be a critical channel for ¿-cell membrane repolarization. We found that Kv2.1-/- mice, a new knockout model, exhibit abnormal glucose homeostasis with a significant resting hypoglycemia and increased insulin secretion in response to physiological steps in glucose concentration. The islets have wide and aberrant action potentials (APs). Surprisingly the Kv2.1-/- islets remain sensitive to tetraethylammonium, a blocker of Kv channels and Ca2+-activated K+ channels (KCa). These results reveal that other K+ channels participate in membrane repolarization and generation of APs, and could be targets for regulation. We propose to study the properties of these Kv currents not previously studied in normal mouse models in wild type and Kv2.1-/- mice with the following two specific aims: Aim 1. To define mechanisms underlying regulation of insulin secretion and calcium signaling by Kv channels. Aim 2. To define the molecular identity of repolarizing K+ channels expressed in ¿-cells and understand the role they play in ¿-cell excitation-secretion coupling. The results of these studies will enhance our understanding of the importance of Kv channels in insulin secretion and their role in the pathogenesis and potential treatment of diabetes. PUBLIC HEALTH RELEVANCE: Diabetes Mellitus is an important health problem, caused by abnormal insulin secretion relative to the degree of insulin resistance leading to numerous complications. This project addresses important biophysical aspects of the regulation of insulin secretion focusing on how potassium ion movement in and out of the cell controls insulin secretion.

描述（由申请人提供）：本修订提案的总体目标是阐明在正常和糖尿病状态下将细胞电兴奋性与葡萄糖诱导的胰岛素分泌（GSIS）偶联的分子机制。我们试图测试关于电压依赖性K+（Kv）通道在调节电活动和触发GSIS的细胞内游离Ca 2+浓度（[Ca 2 +]i）变化中的作用的假设。一旦代谢导致产生动作电位（AP）的KATP通道关闭，Kv通道在细胞膜的复极化中起着独特的作用，导致胰岛素分泌所需的Ca 2+瞬变。用于治疗糖尿病的肠促胰岛素激动剂通过PKA依赖性机制降低Kv电流，但所涉及的Kv通道的身份仍不明确。Kv通道Kv2.1是<$-细胞中主要的Kv通道，被认为是<$-细胞膜复极化的关键通道。我们发现，Kv2.1-/-小鼠，一种新的基因敲除模型，表现出异常的葡萄糖稳态与一个显着的静息低血糖和增加胰岛素分泌响应葡萄糖浓度的生理步骤。胰岛具有广泛和异常的动作电位（AP）。令人惊讶的是，Kv2.1-/-胰岛对Kv通道和Ca 2+激活的K+通道（KCa）的阻断剂四乙基铵保持敏感。这些结果表明，其他K+通道参与膜复极和AP的产生，并可能是调节的目标。我们建议研究这些Kv电流的性质，以前没有研究在正常小鼠模型中的野生型和Kv2.1-/-小鼠具有以下两个具体目标：目的1。明确Kv通道调节胰岛素分泌和钙信号传导的机制。目标2.确定<$-细胞中表达的复极化K+通道的分子身份，并了解它们在<$-细胞兴奋-分泌偶联中的作用。这些研究的结果将增强我们对Kv通道在胰岛素分泌中的重要性及其在糖尿病发病机制和潜在治疗中的作用的理解。公共卫生相关性：糖尿病是一个重要的健康问题，由相对于胰岛素抵抗程度的异常胰岛素分泌引起，导致许多并发症。这个项目解决了重要的生物物理方面的调节胰岛素分泌，重点是如何钾离子运动进出细胞控制胰岛素分泌。