SUR1 (ABCC8) AND ATRIAL KATP CHANNELS

描述(由申请人提供)：磺脲类受体(SURS)在心脏代谢和兴奋性之间提供了独特的联系。该项目的前期工作表明，SUR1和SUR2基因在心脏中都有表达，在不同的区域具有空间和病理变异性。由于这些亚基对KATP通道具有不同的代谢和药理敏感性，这意味着心肌KATP通道的激活可能因疾病状态而不同。其他研究表明，这些蛋白质的差异剪接版本可能在心脏中表达，并赋予不同的功能后果。新的细胞生物学工具和转基因动物的发展使我们能够产生广泛的初步数据，这些数据导致我们提出使用生化、细胞生物学和生理学方法进行实验，以充分了解心脏中SuR亚单位变异的性质和作用。他们的动机是基于对转基因动物的分析，我们在小鼠心脏内发现了不同的亚单位表达和随之而来的功能差异，包括表达控制的机制研究，以及模型系统和人类心脏中的功能后果研究。

DESCRIPTION (provided by applicant): Sulfonylurea receptors (SURs) provide a unique link between cardiac metabolism and excitability. Previous efforts on this project have demonstrated that both SUR1 and SUR2 genes are expressed in the heart, with spatial and pathological variability in different regions. Because these subunits confer different metabolic and pharmacologic sensitivities to KATP channels, this realization means that cardiac KATP channel activation may vary regionally and with disease state. Additional studies suggest that differentially spliced versions of the proteins may be expressed in the heart and confer differential functional consequences. The development of novel cell biological tools and transgenic animals have allowed us to generate extensive preliminary data that lead us to propose experiments using biochemical, cell biological and physiological approaches to reach a full understanding of the nature and role of SUR subunit variation in the heart. They are motivated by our discovery of differential subunit expression and consequent functional differences within the mouse heart based on analysis of genetically modified animals, and encompass both mechanistic studies of expression control, and studies of the functional consequences in model systems and human hearts.