NEURAL CONTROL OF ION CHANNELS AND AUTONOMIC RESPONSE

离子通道的神经控制和自主反应

• 批准号: 6335058
• 负责人: RICHARD B ROBINSON
• 金额: $ 29.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6335058
• 关键词: age difference; biological signal transduction; calcium channel; cardiac myocytes; electrophysiology; gene expression; heart contraction; heart electrical activity; heart innervation; heart pharmacology; heart rhythm; histogenesis; laboratory rabbit; laboratory rat; membrane channels; membrane potentials; muscle cells; neuropeptide Y; newborn animals; potassium channel; protein kinase C; sodium channel; tissue /cell culture; voltage /patch clamp; voltage gated channel

The overall goal is to define the nature and time course of developmental changes in myocardial ion channel function and autonomic responsiveness, and the mechanism(s) through which these changes are achieved. This goal derives from our hypothesis (based on prior work under this PPG) that are sympathetic innervation exerts a trophic influence on cardiac phenotype maturation, thereby inducing significant changes in myocardial electrophysiology and pharmacology. Recent studies under Project D have identified important developmental changes in ionic currents contributing to sinus node impulse initiation (I/Na), ventricular pacemaking (I/f), the plateau (I/CaL) and phase 3 repolarization (I/K1, I/to). Yet the factors, neuronal and otherwise, that are responsible for regulation of these currents are unknown. Project D will determine the nature of the developmental changes in these currents and extent to which, and mechanism by which, innervation contributes to them. To attain this end we use an in vitro approach that permits the direct control of the micro-environment of myocardial cell in culture, and includes the ability to functionally innervate myocytes in culture with sympathetic neurons. Our first aim, which follows from our recent discovery of a neuronal type I-like Na current in neonatal sinus node myocytes, is to determine the implications of this current for autonomic control of normal sinus rhythm in the young heart, and investigate the factor(s) responsible for the age-dependent loss of this current. Our second aim, which arises from recent data on the developmental and innervation dependent shift in the activation voltage pacemaker current I/f, includes studying the time course of the developmental shift in I/f, the mechanism by which innervation modulates the current (i.e. the neural factor) and the basis of the change in current-in particular the role of protein kinase C and phosphorylation. Our third aim, which derives from data indicating that innervation is likely to regulate I/CaL, via neurally released NPY, is to determine the mechanism by which innervation and NPY modulate I/CaL, as well as to further elucidate the contribution of sympathetic innervation to the developmental maturation of the repolarizing currents I/k1 and I/to. By studying the changes in heart rate and repolarization that occur developmentally and their sympathetic modulation, we will not only improve our understanding of the mechanism that regulate normal electrophysiological function, but will provide a framework for understand how arrhythmogenic interventions-studied in other Projects-impact on normal function.

总体目标是确定发展的性质和时间进程， 心肌离子通道功能和自主反应性的变化， 以及实现这些变化的机制。这一目标 来自我们的假设（基于此PPG下的先前工作）， 交感神经支配对心脏表型有营养作用 成熟，从而诱导心肌细胞的显著变化， 电生理学和药理学。最近在项目D下进行的研究 确定了重要的发展变化的离子电流贡献 窦房结冲动启动（I/Na）、心室起搏（I/f）、 平台期（I/CaL）和3相复极化（I/K1，I/to）。然而，这些因素， 神经元和其他负责调节这些 电流是未知的。项目D将决定 这些电流的发展变化及其程度和机制 其中，神经支配对它们有贡献。为了达到这个目的，我们使用一个in 体外方法，允许直接控制的微环境， 培养的心肌细胞，包括功能性 在与交感神经元一起培养中使肌细胞受神经支配。我们的第一个目标， 这是因为我们最近发现了一种神经元I型样Na+， 电流在新生儿窦房结肌细胞，是为了确定的影响， 这种电流的自主控制正常窦性心律的年轻人 心脏，并调查与年龄相关的因素 失去这股电流。我们的第二个目标，来自最近的数据， 激活电压的发育和神经支配依赖性变化 起搏器电流I/f，包括研究 I/f的发展变化，神经支配调节的机制 电流（即神经因素）和变化的基础， 电流-特别是蛋白激酶C和磷酸化的作用。 我们的第三个目标，来自数据表明，神经支配是 可能通过神经释放的NPY调节I/CaL， 神经支配和NPY调节I/CaL的机制， 进一步阐明了交感神经支配对神经系统的作用。 复极化电流I/k1和I/to的发育成熟。通过 研究心率和复极的变化， 发展和他们的交感神经调制，我们不仅会改善 我们对调节正常的 电生理功能，但将提供一个框架，了解 在其他项目中研究的致瘤干预措施如何影响 正常功能。