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（由适用提供）：这项修订的建议的总体目标是阐明正常和糖尿病状态下的分子机制与葡萄糖诱导的胰岛素分泌（GSIS）耦合电气兴奋。我们试图检验有关依赖电压依赖性K+（KV）通道在调节性电活动中的作用以及触发GSIS的细胞内游离Ca2+浓度（[Ca2+] i）的变化的假设。一旦新陈代谢导致关闭KATP通道产生动作电位（APS），KV通道就在复制–细胞膜中发挥了独特的作用，从而导致胰岛素分泌所需的Ca2+瞬变。用于治疗糖尿病的肠毒素激动剂通过依赖于PKA的机制减少KV电流，但是所涉及的KV通道的身份仍然不确定。 KV通道KV2.1是»细胞中的主要KV通道，被认为是`` - 细胞膜复极的关键通道。我们发现，Kv2.1 - / - 小鼠是一种新的基因敲除模型，暴露了异常的葡萄糖稳态，具有明显的静息低血糖和增加的胰岛素分泌，以响应葡萄糖浓度的物理步骤。胰岛具有广泛而异常的动作电位（AP）。令人惊讶的是，KV2.1 - / - 小岛对四乙基铵（KV通道的阻滞剂和Ca2+激活的K+通道（KCA））仍然敏感。这些结果表明，其他K+通道参与了膜复制和AP的产生，并且可能是调节的靶标。我们建议研究以下两个具体目的的野生型小鼠模型中未研究的这些KV电流的性质：目标1。定义KV通道对胰岛素分泌和钙信号传导的调节的基础机制。目的2。定义在``````'''中表达的重复k+通道的分子身份，并了解它们在```````''' - 细胞兴奋 - 分泌耦合中扮演的作用。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的发病机理和潜在治疗中的作用。公共卫生相关性：糖尿病是一个重要的健康问题，是由胰岛素耐药性程度异常导致胰岛素抗性的异常分泌引起的。该项目介绍了调节胰岛素分泌的重要生物物理方面，重点是钾离子如何进出细胞控制胰岛素分泌。