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（由申请人提供）：心脏病仍然是美国和其他发达国家的主要死亡原因。大多数死亡与心肌缺血和心律失常有关。心肌中的肌膜KATP通道随着心率升高和在应激条件下（如心脏缺血）打开。KATP通道的开放调节动作电位时程和细胞内Ca ~（2+）。因此，它们在确定收缩性、心律失常和电传导方面具有重要作用。已证实KATP通道开放在应激期间保护心脏。然而，对KATP通道在缺血、再灌注和缺血预处理中的功能缺乏详细的了解，这阻碍了治疗策略的发展。我们的初步数据表明，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。这一提议是由我们的初步观察结果驱动的，即a）缺血预处理防止缺血诱导的KATP通道内化，以及B）在KATP通道亚基Kir6.2心脏特异性敲除的小鼠中，缺血预处理对梗死面积的保护作用被消除。我们推测，通过特定的亚细胞运输途径增强KATP通道表面密度是缺血预处理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）和在缺血性损伤期间恢复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，以了解KATP通道在心脏中的新作用，并将提供在缺血预处理期间的心脏保护功能的分子见解。