NFAT-induced Regional Variations in Kv4 Channel Expression in Heart

NFAT 诱导的心脏 Kv4 通道表达的区域变异

• 批准号: 7787476
• 负责人: Luis F Santana
• 金额: $ 39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-20 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787476
• 关键词: Address; Arts; Biological; Biological Assay; Bioluminescence; Calcineurin; Calcium Signaling; Cardiac Myocytes; Cells; Confocal Microscopy; Data; Development; Disease; Egg Proteins; Electrophysiology (science); Failure; Gene Expression; Goals; Health; Heart; Heart Hypertrophy; Heterogeneity; Hypertrophy; Knockout Mice; Kv4 channel; Lead; Left; Left ventricular structure; Mediating; Membrane; Modeling; Molecular; Movement; Muscle Cells; Myocardial; Physiological; Play; Probability; Regulation; Reporting; Research Personnel; Role; Series; Signal Transduction; Techniques; Telemetry; Testing; Time; Transgenic Mice; Translating; Variant; Ventricular; Work; base; calcineurin phosphatase; luminescence; novel; programs; regional difference; research study; transcription factor; transcription factor NF-AT c3; voltage

DESCRIPTION (provided by applicant): Voltage-gated K+ (Kv) currents are differentially distributed across the left ventricular wall. Kv4 currents are larger in left ventricular epicardial (EPI) cells than in endocardial (ENDO) cells. This non-uniform distribution of Kv4 channel function is essential for normal myocardial repolarization. We recently reported that variations in [Ca2+]i are transduced into changes in Kv4 expression through the activation of the Ca2+-sensitive phosphatase calcineurin and the transcription factor NFATc3. This led to our discovery that differential [Ca2+]i/calcineurin/NFATc3 signaling across the left ventricular free wall underlies transmural variations in Kv4 expression. However, the mechanisms underlying regional differences in [Ca2+]j, calcineurin, and NFATc3 signaling are poorly understood. The work proposed in this application employs a series of novel techniques and approaches developed by our group to address these important issues. Our preliminary data suggest that the proposed experiments are not only feasible but will provide new fundamental information regarding Kv channel regulation in the heart. The proposed work addresses three specific hypotheses. First, we will test the hypothesis that regional variations in [Ca2+]j underlie heterogeneous calcineurin activity in the ventricle. Second, we will test the hypothesis that local and global [Ca2+]i signals modulate NFAT translocation and gene expression in ventricular myocytes. We will then use these data to determine how variations in [Ca2+]j signals between ENDO and EPI cells lead to regional differences in NFAT activity. Finally, we will test the hypothesis that calcineurin/NFATc3 signaling is essential for maintaining Kv current heterogeneity in the ventricle. Taken together, this work will provide the first integrated view of calcium signaling, excitability, and contractility in the heart and significantly enhance our understanding of the basic mechanisms, which regulate Kv channel function in health and disease.

描述（由申请人提供）：电压门控 K+ (Kv) 电流在左心室壁上有差异分布。左心室心外膜 (EPI) 细胞中的 Kv4 电流大于心内膜 (ENDO) 细胞中的 Kv4 电流。 Kv4 通道功能的这种不均匀分布对于正常心肌复极至关重要。我们最近报道，[Ca2+]i 的变化通过 Ca2+ 敏感磷酸酶钙调神经磷酸酶和转录因子 NFATc3 的激活转导为 Kv4 表达的变化。这导致我们发现跨左心室游离壁的差异性 [Ca2+]i/钙调神经磷酸酶/NFATc3 信号传导是 Kv4 表达跨壁变化的基础。然而，人们对 [Ca2+]j、钙调磷酸酶和 NFATc3 信号传导区域差异的机制知之甚少。本申请中提出的工作采用了我们小组开发的一系列新技术和方法来解决这些重要问题。我们的初步数据表明，所提出的实验不仅可行，而且将提供有关心脏 Kv 通道调节的新基本信息。拟议的工作解决了三个具体假设。首先，我们将检验以下假设：[Ca2+]j 的区域差异是心室中异质钙调神经磷酸酶活性的基础。其次，我们将检验局部和整体 [Ca2+]i 信号调节心室肌细胞中 NFAT 易位和基因表达的假设。然后，我们将使用这些数据来确定 ENDO 和 EPI 细胞之间 [Ca2+]j 信号的变化如何导致 NFAT 活性的区域差异。最后，我们将检验钙调神经磷酸酶/NFATc3 信号传导对于维持心室 Kv 电流异质性至关重要的假设。总而言之，这项工作将首次提供心脏钙信号传导、兴奋性和收缩性的综合视图，并显着增强我们对调节健康和疾病中 Kv 通道功能的基本机制的理解。