MOLECULAR TARGETING OF CA2+ AND K+ CHANNELS IN HEART

本项目提出的研究的总体目标是确定心脏离子通道蛋白和有机药物分子的分子特性，这些分子特性将允许有针对性地控制心肌细胞中的钙进入，特别是在梗死心脏边界区存活的心肌细胞。这一目标的动机来自该计划其他项目的数据，其中显示，增加l型钙通道电流可以防止梗死犬心脏的再入性心动过速，并且在梗死心脏的心外膜边界区（EBZ）存活的心外膜细胞中，关键离子通道（Na+， Ca2+和K+）的功能和分子特性发生了改变。因此，该项目的总体目标是提供对机制的分子洞察，从而允许更精确地靶向药物来控制钙进入这些细胞。因此，这个项目有三个具体目标。(1)确定钙进入心脏和平滑肌l型钙通道的分子决定因素；(2)验证药物诱导的l型Ca2+通道失活动力学变化是调节钙进入靶细胞的有力机制的假设；(3)验证正常细胞和EBZ细胞中不同的1Ks通道亚基组装对表达通道具有独特的药理学和调节特性的假设。这些信息将为靶向控制钙进入EBZ细胞提供分子基础，结合该计划其他项目获得的数据，将为开发新的抗心律失常疗法提供框架，以控制缺血时的再入性心律失常。

Description (Adapted from Applicant's Abstract) The overall goal of the research proposed in this project is to identify molecular properties of cardiac ion channel proteins and organic drug molecules that will allow targeted control of calcium entry in cardiac myocytes in general and in myocytes surviving in the border zone of infarcted hearts in particular. Motivation for this goal comes from data in other projects of this program where it was shown that increasing L-type calcium channel current may prevent reentrant tachycardia in the infarcted canine heart, and that functional and molecular properties of key ion channels (Na+, Ca2+, and K+) are altered in epicardial cells that survive in the epicardial border zone (EBZ) of infarcted hearts. The overall goal of this project is thus to provide molecular insight into mechanisms that would permit more precise targeting of drugs to control calcium entry in these cells. There are thus three specific aims of this project. (1) to identify molecular determinants that target potentiation of calcium entry to cardiac vs. smooth muscle L-type calcium channels: (2) to test the hypothesis that drug-induced changes in L-type Ca2+ channel deactivation kinetics is a powerful mechanism of modulating calcium entry into targeted cells; and (3) to test the hypothesis that subunit assembly of 1Ks channel, which may differ between normal and EBZ cells, confers unique pharmacological and regulatory properties upon expressed channels. Together this information will provide a molecular basis for targeting control of calcium entry into cells of the EBZ which, in combination with the data obtained from other Projects of this program will provide the framework for the development of novel anti-arrhythmic therapy to control reentrant arrhythmias in ischemia.