Structure-Function of the Cardiac Sodium Channel

描述（由申请人提供）：Na通道在可兴奋细胞中的中心作用使其在正常和异常行为中发挥关键作用。它的门控是一个复杂的系统，即使是轻微的门控功能障碍也会导致衰弱性疾病或死亡。该提案的长期目标是了解心脏Na通道的结构和功能，作为正常和异常兴奋和传导的关键贡献者，以及作为治疗心律失常的药物靶点。这是第一次有足够的信息，我们可以希望将药物限制渗透的作用与它们影响门控的作用联系起来。未来五年的提案目标是：1）确定激活过程中S6片段的构象变化; 2）确定快速失活过程中S6的构象变化及其与S4运动的关系; 3）确定局部麻醉药物结合的分子特征和作用机制; 4）定位S6和S5螺旋上与S4片段相关的表面残基。提出的实验将联合收割机分子技术与电生理学（主要是全细胞离子和门控电流记录）和分子建模相结合，以识别响应于S4电压传感器运动和药物结合的内孔S5和S6段的构象变化。该提案的一个关键要素是将我们自己和其他人的实验数据整合到一个分子模型中， < 药物结合、门控和内孔的构象。

DESCRIPTION (provided by applicant): The central role of Na channels in excitable cells gives it a critical role in normal and abnormal behavior. Its gating is a complex system, and even modest dysfunction of gating results in debilitating disease or death. The long term goal of this proposal is to understand the structure and function of the cardiac Na channel as a key contributor to normal and abnormal excitation and conduction and as a target of drugs to treat arrhythmias. For the first time sufficient information is available that we can hope to connect the action of drugs to limit permeation with their action to affect gating. The goals of the proposal for the next five years are to 1) Identify the conformational changes of S6 segments during activation; 2) Identify conformational changes in S6 during fast inactivation and their relation to S4 movements; 3) Determine the molecular features of local anesthetic drug binding and the mechanism of action; and 4} Locate superficial residues on S6 and S5 helices in relation to S4 segments. The experiments proposed combine molecular techniques with electrophysiology, principally whole cell ionic and gating current recordings, and molecular modeling to identify conformational changes in the inner pore S5 and S6 segments in response to S4 voltage sensor movement and drug binding. A key element of the proposal is to integrate: experimental data, both our own and that of others, into a molecular model of the relationship between < drug binding, gating, and the conformation of the inner pore.