CA Permeable Na Channels & Cardiac Cell Excitation

描述（由申请人提供）：ICa（TTX）是一种钠电流成分，见于许多神经和心脏制剂中。在每种情况下，发现ICa（TTX）通道在该细胞类型中表达与钠电流主体不同的门控和不同的通透性。对于大鼠心室细胞，我们已经表明，ICa（TTX）通道是由编码经典心脏钠电流的不同基因编码的。正如所期望的那样，清晰电流成分的存在，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。与传统的心脏钠电流相比，ICa（TTX）在更负的电位范围内激活。然后，它应该放大传递到心室细胞的去极化，从而为心脏动作电位提供直接触发。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，我们有了一个新的通道，由一个独特的基因编码，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需要对其进行广泛的研究。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，它的缓慢失活特性（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）通道对一价离子和二价离子的选择性顺序。电流元件的特性是由它的选择性和门控特性决定的。这将是首次确定表达高钙渗透性的天然钠通道的碱离子选择性，并可能对典型钠通道中离子选择性的结构基础的新兴图景具有重要意义。（iii）通过使用反义寡核苷酸针对已知在心脏细胞中表达的几种钠通道亚型，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）的性质，看看其性质的改变是否与病理状况相关。

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.