SUR1 (ABCC8) AND ATRIAL KATP CHANNELS

描述(申请人提供)：ATP敏感性K+(KATP)通道在整个心肌中以高密度存在。本项目旨在了解心房和心室中不同的KATP通道特性的细胞和分子基础，并了解这些通道的药理和病理生理作用的这种不同构成的后果。初步研究表明，磺酰脲受体(SUR)亚型是组织特异性KATP组成和功能的关键决定因素。这些研究还强调了SUR1和SUR2A对KATP通道的不同调节，其中SUR1在生理条件下产生更活跃的通道。大量的初步数据表明，虽然SUR2a可能是心室中的主要SURR亚单位，但SUR1是心房中必需的亚单位，因此导致了这两个组织中不同的药理激活谱。初步研究还表明，虽然Kir6.2基因敲除对缺血反应有不利影响，但SUR1基因敲除是有益的。为了扩展这些初步发现并探索其意义，提出了三个具体的目标，以解决以下问题：(1)组成心脏不同区域KATP通道的亚单位是什么；(2)心房KATP电导的病理生理和药理学特性是什么；(3)心房KATP在心脏病理生理学和心律失常发生中的作用是什么？为了实现这些目标，人们开发了一系列新的工具，包括一种新的特异性抗SUR1抗体，以及通过各种合作开发的适当的模型系统。该项目将使用多层次的方法来解决这个问题--从转录本和蛋白质的分子分析到细胞、组织和整个动物的研究。拟议的实验结果将确定心脏KATP通道的区域组成，以及这些通道在心律失常和心脏对缺血的反应中的作用。公共卫生相关性：心肌缺血，由于冠状动脉血管阻塞而导致的血流不足，是心脏病和死亡的主要原因。因此，了解心脏对缺血的反应对于开发适当的治疗方法至关重要。此外，心律失常，特别是房颤，是发病率和死亡率的主要原因。心肌细胞膜上的ATP敏感性钾通道(KATP)受细胞代谢状态的复杂调控。正因为如此，这些通道是缺血的主要传感器，将代谢状态与电活动联系起来，从而与心脏功能联系起来。它们以非常高的密度存在，当被激活时可导致折返性心律失常，包括房性心律失常。因此，该项目目标的实现--了解心脏不同区域KATP通道的组成，以及这种不同组成的功能后果--将为开发治疗心肌缺血和心律失常的合理疗法提供必要的信息。

DESCRIPTION (provided by applicant): ATP-sensitive K+ (KATP) channels are present at high density throughout the myocardium. This project seeks to understand the cellular and molecular basis for differential KATP channel properties in the atrium and ventricle, and to understand the consequences of this differential make-up for the pharmacological and pathophysiological role of these channels. Preliminary studies show that sulfonylurea receptor (SUR) isoforms are critical determinants of tissue-specific KATP make-up and function. These studies also highlight differential regulation of KATP channels by SUR1 and SUR2A with SUR1 generating more active channels under physiological conditions. Extensive preliminary data indicate that, while SUR2A is likely the primary SUR subunit in the ventricle, SUR1 is a requisite subunit in the atrium, thereby giving rise to the differential pharmacological activation profiles in the two tissues. Preliminary studies also show that, while Kir6.2 knockout has detrimental consequences for the response to ischemia, knockout of SUR1 is beneficial. In order to extend these preliminary findings and explore their implications, three specific aims are proposed, addressing the following questions: (1) What are the subunits that make up the KATP channel in different regions of the heart; (2) What are the pathophysiological and pharmacological properties of the atrial KATP conductance; (3) What is the role of atrial KATP in cardiac pathophysiology and arrhythmia generation? In order to achieve these aims, a series of novel tools have been developed, including a novel specific anti-SUR1 antibody, and appropriate model systems developed through various collaborations. The project will use a multi-level approach to the problem-from molecular analysis of transcripts and proteins to cellular, tissue and whole animal studies. The results of the proposed experiments will define the regional make-up of the cardiac KATP channel and the role of these channels in the generation of arrhythmias and the cardiac response to ischemia. PUBLIC HEALTH RELEVANCE: Relevance Myocardial ischemia, lack of blood flow resulting from blockade of coronary blood vessels, is a major cause of cardiac disease and death. Understanding the cardiac response to ischemia is thus critical for development of appropriate therapies. In addition, cardiac arrhythmias, particularly atrial fibrillation, are major causes of morbidity and mortality. ATP-sensitive potassium channels (KATP) in the heart cell membranes are regulated in a complex way by the cellular metabolic state. Because of this, these channels are major sensors of ischemia, linking metabolic state to electrical activity and hence to cardiac function. They are present at very high density and when activated can lead to re-entrant arrhythmias, including atrial arrhythmia. Achievement of the goal of this project-understanding of the make-up of KATP channels in different regions of the heart, and the functional consequences of this differential make-up-will thus provide essential information that will lead to the development of rational therapies for the treatment of cardiac ischemia and arrhythmias.