SUR1 (ABCC8) AND ATRIAL KATP CHANNELS

描述（由申请方提供）：磺酰脲类受体（SUR）在心脏代谢和兴奋性之间提供独特的联系。该项目的前期工作已经证明，SUR1和SUR2基因都在心脏中表达，在不同区域具有空间和病理变异性。由于这些亚基赋予KATP通道不同的代谢和药理学敏感性，这一认识意味着心脏KATP通道激活可能因区域和疾病状态而异。其他研究表明，差异剪接的蛋白质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，使我们提出的实验，使用生物化学，细胞生物学和生理学的方法，以达到一个完整的理解的性质和作用的SUR亚基变异的心脏。他们的动机是我们发现的差异亚基表达和随之而来的功能差异的基础上分析转基因动物的小鼠心脏，并包括表达控制的机制研究，以及在模型系统和人类心脏的功能后果的研究。

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.