K+ Channel Expression in Pancreatic Beta-Cells

胰腺 β 细胞中 K 通道的表达

• 批准号: 7813915
• 负责人: Louis H. Philipson
• 金额: $ 32.4万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813915
• 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）：该修订提案的总体目标是阐明耦合电兴奋性的分子机制 ¿ -细胞在正常和糖尿病状态下葡萄糖诱导的胰岛素分泌（GSIS） 我们试图检验有关电压依赖性 K+（Kv）通道在调节电活动和细胞内游离 Ca2+ 浓度（[Ca2+]i）变化中的作用的假设。 ），一旦新陈代谢导致产生动作电位（AP）的 KATP 通道关闭，Kv 通道在复极化 ¿细胞膜，产生胰岛素分泌所需的 Ca2+ 瞬变，用于治疗糖尿病，通过 PKA 依赖性机制降低 Kv 电流，但所涉及的 Kv 通道的身份仍不清楚。Kv 通道 Kv2.1 是主要的 Kv。频道 ¿ -细胞，被认为是 ¿ 的关键通道我们发现，Kv2.1-/- 小鼠（一种新的敲除模型）表现出异常的葡萄糖稳态，并伴有显着的静息低血糖和响应葡萄糖浓度的生理步骤而增加的胰岛素分泌。令人惊讶的是，Kv2.1-/- 胰岛仍然对四乙铵（Kv 通道和 Ca2+ 激活的 K+ 通道的阻断剂）敏感。 (KCa)。这些结果表明其他 K+ 通道参与膜复极化和 AP 的生成，并且可以作为调节的目标，我们建议研究以前在野生型和 Kv2 的正常小鼠模型中未研究过的这些 Kv 电流的特性。 1-/- 小鼠具有以下两个具体目标： 目标 1. 确定 Kv 通道调节胰岛素分泌和钙信号传导的机制 目标 2. 确定 ¿ 中表达的复极化 K+ 通道的分子特性。 -细胞并了解它们在 ¿ -细胞兴奋-分泌耦合。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：糖尿病是一个重要的健康问题。与胰岛素抵抗程度相关的异常胰岛素分泌导致许多并发症该项目解决了胰岛素分泌调节的重要生物物理方面，重点关注钾离子进出细胞的运动如何控制胰岛素分泌。