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：
7631067
负责人：
Jonathan Satin
金额：
$ 36.63万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-15 至 2009-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7631067
关键词：
Abbreviations Acute Adrenergic Agents Adult Aging Automobile Driving C-terminal Calcium Channel Cardiac Cardiac Myocytes Cell Nucleus Chronic Class Condition Coupled Data Defect Disease Down-Regulation Elements Event Funding Growth and Development function Heart Homeostasis Ion Channel Link Localized 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 Transduction Structure Testing Transcriptional Activation Transducers Up-Regulation Ventricular Work adrenergic cardiogenesis chromatin immunoprecipitation clinically relevant in vitro Model in vivo novel protein expression response sensor trafficking transcription factor

Abbreviations Acute Adrenergic Agents Adult Aging Automobile Driving C-terminal Calcium Channel Cardiac Cardiac Myocytes Cell Nucleus Chronic Class Condition Coupled Data Defect Disease Down-Regulation Elements Event Funding Growth and Development function Heart Homeostasis Ion Channel Link Localized 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 Transduction Structure Testing Transcriptional Activation Transducers Up-Regulation Ventricular Work adrenergic cardiogenesis chromatin immunoprecipitation clinically relevant in vitro Model in vivo novel protein expression response sensor trafficking transcription factor

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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-pharmacologicalblock, 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 subcellular 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.

心肌细胞的CA失调会导致心脏发育缺陷和疾病衰老的心。该提议的长期目标是提供一种分子机制，以解释如何心脏L型CA通道（LTCC）感官和传递信号，表明体内稳态调节心脏心肌细胞。心肌细胞与核向核的信号传导有关。胞质CA 在每个心脏周期期间振幅变化> 10倍，但CA的改变以某种方式被差异化用于长期转录信号。在此资助期间，我们将测试CA渠道活动和是否心脏L型CA通道本身编码长期调节的CA信号传导。在过去的资金期间我们发现RGK长期抑制ICA，L（LTCC电流）和这种RGK抑制ICA，L导致A CAV1.2 mRNA的补偿性上调。这表明ICA，L块可能会发出转录事件在核中。在新的研究中，我们通过表明LTCC-Pharmacolagicblock，确认并扩展了这一概念。但是总体上，内部CA并不是造成心脏发展的责任。同样的行成熟的心脏，LTCC的长期封锁也会引起LTCC和ICA，l的补偿性上调。我们的驱动假设是信号不简单由CA确定，而是由主动CA通道确定。发现 LTCC的移动片段位于原子核或t小管中，加上最近的报告肽是一种转录因子，驱动了令人兴奋的新假设，即LTCC的这一部分调节 LTCC表达。我们将以三个目的研究长期渠道调节的这一方面：1。我们将评估 LTCC结构域的核转运，并确定LTCC活性与亚细胞的相互作用本土化; 2。我们将确定LTCC自动调节自身转录的能力；和3。我们将确定SL CA处理蛋白质的补偿性变化，以响应LTCC阻断。这项工作可能在LTCC函数和下游信号事件之间提供缺失的分子联系。