CA Permeable Na Channels & Cardiac Cell Excitation

CA 渗透性 Na 通道

基本信息

批准号：
7123785
负责人：
C. William Balke
金额：
$ 35.76万
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：
2003-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7123785
关键词：
action potentials antisense nucleic acid atrium calcium channel clinical research electrophysiology heart cell heart conduction system heart electrical activity heart ventricle human tissue laboratory rat mathematics membrane permeability protein isoforms sodium channel

项目摘要

DESCRIPTION (provided by applicant): ICa(TTX) is a sodium current component seen in a number of neural and cardiac preparations. In each case, ICa(TTX) channels were found to express both different gating and different permeability properties from the main body of sodium current in that cell type. For rat ventricular cells we have shown that ICa(TTX) channels are encoded by a different gene from that encoding the classical cardiac sodium current. As expected from the very existence of a clear current component, ICa(TTX) channels do affect the electrical behavior of ventricular cells and can even generate action potentials. ICa(TTX) activates over a more negative range of potentials than the classical cardiac sodium current. It should, then, act to amplify the depolarization delivered to a ventricular cell and so provide the immediate trigger for the cardiac action potential. Owing to this role, ICa(TTX) could be of considerable importance in cardiac arrhythmias and in their control. It has been reported in both human atrial and ventricular cells. We have, then, a new channel encoded by a distinct gene that contributes to cardiac cell electrical behavior. The potential importance of this channel for both normal and pathological cardiac electrophysiology calls for its extensive study. We propose to: (i) Determine the slow inactivation properties of ICa(TTX) and compare them to those of the classical sodium current. The slow inactivation process is critical for determining the stationary state pool of available sodium channels. The expected role of ICa(TTX) as the immediate trigger for the cardiac action potential suggests that its slow inactivation properties (and defects in them) could have disproportionately strong effects on the generation and conduction of the cardiac action potentials. (ii) Quantitatively determine the selectivity sequence of ICa(TTX) channels to both mono- and divalent ions. The characteristics of a current component are determined by it selectivity as well as its gating properties. This will be the first determination of the alkali ion selectivity of a native sodium channel that expresses high calcium permeability and could be of importance for the emerging picture of the structural basis for ion selectivity in typical sodium channels. (iii) Start the molecular identification of ICa(TTX) channels by use of antisense oligonucleotides directed against the several sodium channel isoforms known to be expressed in cardiac cells. (iv) Compare the properties of ICa(TTX) in normal and failing human hearts to see if alterations in its properties correlate with pathological conditions.

描述（由申请人提供）：ICa(TTX) 是在许多神经和心脏制剂中看到的钠电流成分。在每种情况下，ICa(TTX) 通道都表现出与该细胞类型的钠电流主体不同的门控和不同的渗透特性。对于大鼠心室细胞，我们已经证明 ICa(TTX) 通道是由与编码经典心脏钠电流的基因不同的基因编码的。正如从清晰电流分量的存在所预期的那样，ICa(TTX) 通道确实影响心室细胞的电行为，甚至可以产生动作电位。 ICa(TTX) 在比经典心脏钠电流更负的电位范围内激活。然后，它应该起到放大传递到心室细胞的去极化的作用，从而立即触发心脏动作电位。由于这一作用，ICa(TTX) 在心律失常及其控制中可能具有相当重要的作用。在人类心房和心室细胞中都有报道。那么，我们就有了一个由独特基因编码的新通道，该基因有助于心肌细胞的电行为。该通道对于正常和病理心脏电生理学的潜在重要性需要进行广泛的研究。我们建议：（i）确定ICa（TTX）的缓慢失活特性并将其与经典钠电流的慢失活特性进行比较。缓慢的失活过程对于确定可用钠通道的稳态池至关重要。 ICa(TTX) 作为心脏动作电位的直接触发因素的预期作用表明，其缓慢失活特性（及其缺陷）可能对心脏动作电位的产生和传导产生不成比例的强烈影响。 (ii) 定量确定 ICa(TTX) 通道对单价和二价离子的选择性序列。电流组件的特性由其选择性及其选通特性决定。这将是首次测定表现出高钙渗透性的天然钠通道的碱离子选择性，并且对于典型钠通道中离子选择性的结构基础的新兴图像具有重要意义。 (iii) 通过使用针对已知在心肌细胞中表达的几种钠通道亚型的反义寡核苷酸，开始对 ICa(TTX) 通道进行分子鉴定。 (iv) 比较正常和衰竭人类心脏中 ICa(TTX) 的特性，看看其特性的变化是否与病理状况相关。