Mechanisms of Long-term Cardiac Ion Channel Regulation

心脏离子通道的长期调节机制

• 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
• 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

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Ca ~（2+）调节异常与心脏发育缺陷和心脏疾病有关。 衰老的心脏这项提案的长期目标是提供一种分子机制，解释如何 心脏L型钙通道（LTCC）是一种检测和调节心脏内环境稳态的信号通路， 肌细胞心肌细胞提出了一个难题，相对于钙信号的核。胞液Ca 在每个心动周期中，振幅变化>10倍，但Ca的变化以某种方式被差异解码 用于长期转录信号。在此资助期间，我们将测试钙通道活动和 心脏L型Ca通道本身编码Ca信号传导以进行长期调节。在过去的一段时间里，我们 发现RGK长期抑制伊卡，L（LTCC电流），并且这种RGK对伊卡，L的抑制导致 CaV1.2 mRNA代偿性上调。这表明伊卡，L阻断可能是转录事件的信号传导 在细胞核中。在新的研究中，我们证实并扩展了这一观点， 而不是内部钙一般负责干扰心脏发育。沿着同样的路线，在 在成熟心脏，长期阻断LTCC也引起LTCC和伊卡，L的代偿性上调。我们 驱动假说是信号传导不是简单地由Ca决定，而是由活性Ca通道决定。发现 LTCC的移动的片段定位于细胞核或t-小管， 肽是一种转录因子，推动了令人兴奋的新假设，即LTCC的这一片段， LTCC表达。我们将研究这方面的长期渠道管制在三个目标：1。我们将评估 核转位的LTCC结构域，并确定LTCC活性和亚细胞之间的相互作用， 本地化;我们将确定LTCC转录自我调节的能力; 3.我们 将确定SL Ca处理蛋白响应于LTCC阻断的补偿性变化。这项工作 可能在LTCC功能和下游信号事件之间提供缺失的分子联系。