KATP Channel Trafficking and Cardioprotection

KATP 通道运输和心脏保护

• 批准号: 9236252
• 负责人: William A Coetzee
• 金额: $ 7.94万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236252
• 关键词: Action Potentials; Adenosine; Adult; Arrhythmia; Back; Biological Assay; Biotinylation; C-terminal; Cardiac; Cardiac Myocytes; Cause of Death; Cell model; Cell physiology; Cells; Cessation of life; Complex; Confocal Microscopy; Coupled; Data; Defect; Dependence; Developed Countries; Dominant-Negative Mutation; Elements; Endocytosis; Event; Family member; Functional disorder; GLUT4 gene; Health; Heart; Heart Diseases; Heart Rate; Infarction; Injury; Ischemia; Ischemic Preconditioning; Knock-out; Knockout Mice; Mass Spectrum Analysis; Measurement; Mediator of activation protein; Membrane Proteins; Metabolic; Molecular; Mus; Muscle Cells; Mutagenesis; Myocardial Ischemia; Myocardium; Pathway interactions; Pattern; Physiological; Protein Family; Protein Kinase; Proteins; Pump; Reactive Oxygen Species; Recycling; Reperfusion Therapy; Research; Role; Signal Pathway; Specificity; Stress; Surface; Tamoxifen; Tertiary Protein Structure; Transcription Factor AP-2 Alpha; Transgenic Mice; United States; Ventricular; conditioning; density; design; extracellular; heart rhythm; inhibitor/antagonist; insight; mouse model; new therapeutic target; novel; overexpression; patch clamp; prevent; protective effect; therapeutic development; trafficking

 DESCRIPTION (provided by applicant): Heart disease remains the leading cause of death in the United States and other developed countries. Most deaths are associated with cardiac ischemia and arrhythmias. Sarcolemmal KATP channels in the myocardium open with elevated heart rates and during stress conditions, such as cardiac ischemia. Opening of KATP channels modulate the action potential duration and intracellular Ca2+. As such they have an important role in determining contractility, arrhythmias and electrical conduction. It is well established tht KATP channel opening protects the heart during stress. However, a detailed understanding of the KATP channel function during ischemia, reperfusion and ischemic preconditioning is lacking, which hinders the development of therapeutic strategies. Our preliminary data point to novel subcellular localization patterns of KATP channels within the cardiac myocyte. We further find that myocardial ischemia decreases the surface KATP channel density, which reduces the number of channels that are available for cardioprotection. This proposal is driven by our preliminary observations that a) ischemic preconditioning prevents ischemia-induced internalization of KATP channels and that b) the protective effects of ischemic preconditioning on infarct size are abolished in mice with cardiac-specific knockout of the KATP channel subunit, Kir6.2. We hypothesize that enhancing KATP channel surface density through specific subcellular trafficking pathways is an important element of the protective mechanism of ischemic preconditioning. We will investigate molecular mechanisms that stabilize surface KATP channels (Aim 1), cellular processes that regulate internalization (Aim 2) and potential mechanisms to restore the KATP channel surface density during an ischemic insult (Aim 3). The proposed studies will establish a framework in which to understand novel roles of KATP channels in the heart and will provide molecular insights their cardioprotective function during ischemic pre-conditioning.

 描述(申请人提供)：心脏病仍然是美国和其他发达国家的主要死因。大多数死亡与心脏缺血和心律失常有关。心肌中的肌膜KATP通道随着心率的增加而开放，在应激条件下，如心脏缺血。KATP通道开放对动作电位时程和细胞内钙离子有调节作用。因此，它们在确定收缩能力、心律失常和电传导方面具有重要作用。众所周知，KATP通道开放可以在应激状态下保护心脏。然而，对KATP通道在缺血、再灌注和缺血预适应过程中的作用缺乏详细的了解，这阻碍了治疗策略的发展。我们的初步数据指向心肌细胞内KATP通道的新的亚细胞定位模式。我们进一步发现，心肌缺血降低了表面KATP通道密度，从而减少了可用于心脏保护的通道数量。这一建议是由我们的初步观察推动的，即a)缺血预适应阻止缺血诱导的KATP通道内化，以及b)在心脏特异敲除KATP通道亚单位Kir6.2的小鼠中，缺血预适应对心肌梗死面积的保护作用被取消。我们推测，通过特定的亚细胞转运途径增加KATP通道表面密度是缺血预适应保护机制的重要组成部分。我们将研究稳定表面KATP通道的分子机制(目标1)，调节内化的细胞过程(目标2)，以及在缺血损伤期间恢复KATP通道表面密度的潜在机制(目标3)。拟议的研究将建立一个框架，在其中了解KATP通道在心脏中的新角色，并将提供其在缺血预适应期间的心脏保护功能的分子洞察力。