Mechanisms of Long-term Cardiac Ion Channel Regulation

心脏离子通道的长期调节机制

• 批准号: 7758785
• 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
• 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/7758785
• 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; public health relevance; response; sensor; trafficking; transcription factor; 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; public health relevance; response; sensor; trafficking; transcription factor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: These studies show that widely used clinically-relevant drugs that are used to block LTCC may inadvertently exacerbate heart dysfunction by paradoxically increasing LTCC function. This proposal will lead to understanding of a new mechanism whereby ion channels that control cardiac electrical activity also may control long-term signaling pathways that are critical for maintenance of cardiac structure and function.

描述（由申请人提供）：心肌细胞中的CA失调会导致心脏发育缺陷和衰老心脏的疾病。该提案的长期目标是提供一种分子机制，该机制解释了心脏L型CA通道（LTCC）的感觉和传递信号，并传达了稳态调节心肌细胞的信号。心肌细胞与核向核的信号传导有关。在每个心脏周期期间，胞质Ca振幅变化> 10倍，但CA的变化以某种方式被差异解码以用于长期转录信号传导。在此资助期间，我们将测试CA通道活动和心脏L型CA通道本身是否编码CA信号传导以进行长期调节。在过去的资金期间，我们发现RGK长期抑制ICA，L（LTCC电流）和RGK抑制ICA，L导致CAV1.2 mRNA的补偿性上调。这表明ICA，L块可能在核中表明转录事件。在新的研究中，我们证实并扩展了这一概念，证明了LTCC-药理学 - 而不是内部CA，而不是内部CA是造成心脏发展的原因。沿着相同的线，在成熟的心脏中，LTCC的长期阻滞也会引起LTCC和ICA，l的补偿性上调。我们的驾驶假设是，信号不简单由CA确定，而是由主动CA通道确定。 LTCC的移动片段位于核或T小管中的发现，加上最近的报告，即该肽是转录因子驱动LTCC的这一段调节LTCC表达的令人兴奋的新假设。我们将以三个目的研究长期通道调节的这一方面：1。我们将评估LTCC域的核易位，并确定LTCC活性与亚细胞定位之间的相互作用； 2。我们将确定LTCC自动调节自身转录的能力；和3。我们将根据LTCC阻断的响应，确定SL CA处理蛋白的补偿性变化。这项工作可能会在LTCC函数和下游信号事件之间提供缺失的分子联系。公共卫生相关性：这些研究表明，用于阻断LTCC的临床上的广泛使用的药物可能会通过矛盾地增加LTCC功能而无意间加剧心脏功能障碍。该建议将导致对一种新机制的理解，该机制控制心脏电活动还可以控制长期信号通路，这对于维持心脏结构和功能至关重要。