Mechanisms of Long-term Cardiac Ion Channel Regulation

心脏离子通道的长期调节机制

基本信息

批准号：
8290229
负责人：
Jonathan Satin
金额：
$ 36.26万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8290229
关键词：
Abbreviations Acute Adrenergic Agents Adult Aging Automobile Driving C-terminal Cardiac Cardiac Myocytes Cell Nucleus Chronic Coupled Data Defect Disease Down-Regulation Drug usage Elements Event Functional disorder Funding Growth and Development function Heart Homeostasis Ion Channel L-Type Calcium Channels Lead Link Maintenance Messenger RNA Molecular Monomeric GTP-Binding Proteins Muscle Cells Nuclear Nuclear Translocation Pathway interactions Peptides Pharmaceutical Preparations Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Regulation Reporting Signal Pathway Signal Transduction Structure Testing Transducers Up-Regulation Ventricular Work adrenergic cardiogenesis chromatin immunoprecipitation clinically relevant heart electrical activity in vitro Model in vivo novel protein expression response sensor trafficking transcription factor

项目摘要

Ca dysregulation in cardiac myocytes contributes to heart development defects and diseases of the aging heart. The long-term objective of this proposal is to provide a molecular mechanism that explains how cardiac L-type Ca channels (LTCC) sense and transduce signals that homeostatically regulate cardiac myocytes. Cardiac myocytes present a conundrum with respect to Ca signaling to the nucleus. Cytosolic Ca amplitude varies >10-fold during each cardiac cycle, yet alterations of Ca somehow are differentially decoded for longer-term transcriptional signaling. In this funding period we will test whether Ca channel activity and the cardiac L-type Ca channel itself encodes Ca signaling for long-term regulation. In the past funding period we discovered that RGK chronically inhibited ICa,L (LTCC current), and this RGK inhibition of ICa,L resulted in a compensatory up-regulation of CaV1.2 mRNA. This suggests that ICa,L block may signal transcriptional events in the nucleus. In new studies we confirmed and extended this notion by showing that LTCC-pharmacological- block, but not internal Ca in general is responsible for perturbing heart development. Along the same lines, in mature heart, long-term blockade of LTCC also causes a compensatory up-regulation of LTCC and ICa,L. Our driving hypothesis is that signaling is not simply determined by Ca, but by active Ca channels. The discovery that mobile segment of LTCC is localized to the nucleus or t-tubules coupled with the recent report that this peptide is a transcription factor drives the exciting new hypothesis that this segment of the LTCC, regulates LTCC expression. We will study this aspect of long-term channel regulation in three aims: 1. We will assess nuclear translocation of a domain of the LTCC, and determine the interaction between LTCC activity and sub- cellular localization; 2. We will determine the ability of LTCC to auto-regulate itself transcriptionally; and 3. We will determine the compensatory changes of SL Ca handling proteins in response to LTCC blockade. This work may provide a missing molecular link between LTCC function and downstream signaling events.

心肌细胞中的 Ca2+ 失调会导致心脏发育缺陷和心脏疾病衰老的心脏。该提案的长期目标是提供一种分子机制来解释如何心脏 L 型 Ca 通道 (LTCC) 感知和转导稳态调节心脏的信号肌细胞。心肌细胞在向细胞核传递 Ca2+ 信号传导方面存在难题。胞质钙每个心动周期振幅变化 >10 倍，但 Ca 的变化以某种方式被不同地解码用于长期转录信号传导。在本次资助期间，我们将测试 Ca 通道活动和心脏 L 型 Ca 通道本身编码 Ca 信号传导以进行长期调节。在过去的资助期内，我们发现 RGK 长期抑制 ICa,L（LTCC 电流），并且 RGK 对 ICa,L 的抑制导致 CaV1.2 mRNA 的代偿性上调。这表明 ICa,L 块可能发出转录事件信号在细胞核中。在新的研究中，我们证实并扩展了这一概念，表明 LTCC-药理学- 阻滞，但不是内部钙一般负责扰乱心脏发育。沿着同样的思路，在对于成熟的心脏，长期阻断 LTCC 也会导致 LTCC 和 ICa,L 的代偿性上调。我们的驱动假设是信号传导不仅由 Ca 决定，而且由活跃的 Ca 通道决定。发现 LTCC 的移动部分位于细胞核或 T 型小管，加上最近的报告表明，肽是一种转录因子，推动了令人兴奋的新假设，即 LTCC 的这一部分调节 LTCC 表达。我们将从三个目标来研究这方面的长期渠道监管： 1.我们将评估 LTCC 结构域的核易位，并确定 LTCC 活性和亚- 细胞定位； 2.我们将确定LTCC在转录上自动调节自身的能力； 3.我们将确定 SL Ca 处理蛋白响应 LTCC 阻断的代偿性变化。这部作品可能提供 LTCC 功能和下游信号事件之间缺失的分子联系。