CA Permeable Na Channels & Cardiac Cell Excitation

CA 渗透性 Na 通道

• 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
• 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

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，都发现ICA（TTX）通道从该细胞类型中的钠电流主体表达不同的门控和不同的渗透率。对于大鼠心室细胞，我们已经表明ICA（TTX）通道由与编码经典心脏钠电流的基因编码不同。正如明确的电流成分的存在所预期的那样，ICA（TTX）通道确实会影响心室细胞的电气行为，甚至可以产生动作电位。与经典心脏钠电流相比，ICA（TTX）在电势范围更大的电位上激活。然后，它应该起作用，以扩大递送到心室细胞的去极化，从而为心脏作用电位提供直接触发。由于这个角色，ICA（TTX）在心律不齐和控制中可能非常重要。在人心房和心室细胞中都有报道。那么，我们拥有一个由一个不同基因编码的新通道，该基因有助于心脏细胞电行为。该通道对正常和病理心脏电生理学的潜在重要性要求其广泛的研究。我们建议：（i）确定ICA（TTX）的缓慢灭活特性，并将其与经典钠电流进行比较。缓慢的灭活过程对于确定可用钠通道的固定状态池至关重要。 ICA（TTX）作为心脏作用电位的直接触发的预期作用表明，其缓慢的失活特性（以及其中的缺陷）可能对心脏动作电位的产生和传导的影响不成比例。 （ii）定量确定ICA（TTX）通道的选择性序列对单个和二价离子的选择性序列。当前组件的特征取决于IT选择性及其门控性能。这将是表达高钙渗透性的天然钠通道的碱基选择性的首次测定，对于典型钠通道中离子选择性的新兴图片可能是重要的。 （iii）通过使用针对已知在心脏细胞中表达的几种钠通道同工型的反义寡核苷酸来开始对ICA（TTX）通道的分子鉴定。 （iv）比较正常和失败的人心中ICA（TTX）的特性，以查看其特性的改变是否与病理条件相关。

项目成果

Quantitative analysis of a fully generalized four-state kinetic scheme.

• DOI: 10.1529/biophysj.106.081067
• 发表时间: 2006-07
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: L. Goldman