CA Permeable Na Channels & Cardiac Cell Excitation

描述（由申请人提供）：伊卡（TTX）是一种钠电流成分，见于许多神经和心脏制剂。在每种情况下，发现伊卡（TTX）通道表达与该细胞类型中钠电流主体不同的门控和不同的渗透性特性。对于大鼠心室细胞，我们已经表明，伊卡（TTX）通道编码的一个不同的基因从编码经典的心脏钠电流。正如预期的那样，从一个明确的电流成分的存在，伊卡（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。伊卡（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，从而为心脏动作电位提供即时触发。由于这种作用，伊卡（TTX）在心律失常及其控制中可能具有相当重要的意义。在人类心房和心室细胞中都有报道。因此，我们有了一个由一个独特的基因编码的新通道，它有助于心脏细胞的电行为。该通道对正常和病理心脏电生理的潜在重要性要求对其进行广泛的研究。我们建议：（i）确定缓慢失活特性的伊卡（TTX），并比较它们的经典钠电流。缓慢失活过程对于确定可用钠通道的稳态池至关重要。伊卡（TTX）作为心脏动作电位的直接触发器的预期作用表明，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)定量测定伊卡（TTX）通道对一价和二价离子的选择性顺序。电流分量的特性由其选择性以及其选通特性决定。这将是第一次确定的碱性离子选择性的天然钠通道，表达高钙渗透性，并可能是重要的新兴图片的离子选择性的结构基础，在典型的钠通道。(iii)通过使用针对已知在心脏细胞中表达的几种钠通道亚型的反义寡核苷酸，开始伊卡（TTX）通道的分子鉴定。(iv)比较正常和衰竭的人类心脏中伊卡（TTX）的性质，看看其性质的改变是否与病理条件相关。

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.