Mechanisms of sulfonylurea receptor mediated cardiomyopathy

描述（申请人提供）：ATP敏感性钾（KATP）通道通过直接核苷酸结合对细胞内能量状态做出反应。KATP通道感知细胞内ADP含量，并作为响应调节膜电位。在心室心肌细胞中发现的主要KATP调节组分是由Abcc 9基因编码的磺酰脲受体（SUR）-2。与其他ABC转运蛋白一样，SUR 2是具有两个核苷酸结合折叠的多跨膜蛋白。格列本脲是一种磺酰脲类拮抗剂，通常用于治疗糖尿病，尽管据报道这类药物会增加糖尿病患者的心血管风险。通过SURs发挥作用的药物的临床应用，以及开发利用这些途径的其他药物的可能性，都表明需要更好地理解SURs及其作用，特别是在高能量需求组织（如心脏）中的作用。Abcc 9/SUR 2基因中的突变引起扩张型心肌病，并且最近与Cantu综合征（一种罕见的多系统疾病，包括心脏肥大）有关（Harakalova等人，2012;货车Bon等人，2012年）。Abcc 9基因经过选择性剪接产生SUR 2，一种特征性的ATP结合盒蛋白，以及一种较小的55 KDa蛋白，我们称之为SUR 2 - 55。与SUR 2一样，SUR 2 -55可以与伴侣钾通道偶联，但SUR 2 -55富集在线粒体中。Abcc 9基因的缺失使SUR 2 -55保持完整，导致冠状动脉血管痉挛、高血压、心源性猝死。相比之下，以消融SUR 2和SUR 2 -55的方式缺失Abcc 9导致出生后前10天的新生儿心肌病。已知新生心脏在此窗口期间从葡萄糖代谢转变为氧化代谢，并且这种转变在Abcc 9缺失小鼠中受损。在单独的实验中，我们发现心脏中SUR-55的转基因过表达保护心脏免受缺血再灌注损伤。我们推测，Abcc 9编码的蛋白质，通过KATP通道，有助于代谢平衡，特别是在应激条件下，如新生儿心脏和缺血心肌。新生儿和成人心肌中的Abbc 9消融将用于定义SUR 2复合物及其在心脏中的作用。

DESCRIPTION (provided by applicant): ATP-sensitive potassium (KATP) channels response to the intracellular energy state of the cell through directly nucleotide binding. KATP channels sense intracellular ADP content and, in response, regulate membrane potential. The major KATP regulatory component found in the ventricular cardiomyocyte is the sulfonylurea receptor (SUR)-2, encoded by the Abcc9 gene. Like other ABC transporter proteins, SUR2 is a multi- transmembrane protein with two nucleotide-binding folds. Glyburide, a sulfonylurea antagonist, is used commonly to treat diabetes, although this class of medications has been reported to increase cardiovascular risk in diabetics. The clinical use of drugs that act through the SURs, as well as the possibility to develop additional agents that utilize these pathways, argues for improved understanding of SURs and their role especially in high energy demand tissue like the heart. Mutations in the Abcc9/SUR2 gene cause dilated cardiomyopathy and more recently have been linked to Cantu syndrome, a rare multisystem disorder that includes cardiomegaly (Harakalova et al., 2012; van Bon et al., 2012). The Abcc9 gene undergoes alternative splicing to produce SUR2, a characteristic ATP binding cassette protein, and also a smaller 55 KDa protein, which we termed SUR2- 55. Like SUR2, SUR2-55 can couple with the partner potassium channel but SUR2-55 is enriched in mitochondria. Deletion of the Abcc9 gene in a manner that leaves SUR2-55 intact, leads to coronary artery vascular spasm, hypertension, sudden cardiac death. In contrast, deletion of Abcc9 in a manner that ablate both SUR2 and SUR2-55 leads to neonatal cardiomyopathy in the first 10 days of life. The newborn heart is known to transition from glucose to oxidative metabolism during this window, and this transition is impaired in Abcc9 deleted mice. In separate experiments, we found that transgenic overexpression of SUR-55 in the heart protects the heart from ischemic reperfusion injury. We hypothesize that Abcc9-encoded proteins, through KATP channels, contribute to the metabolic balance especially under stress conditions such as the newborn heart and in ischemic myocardium. Ablation of Abbc9 in the newborn and adult myocardium will be used to define SUR2 complexes and their role in the heart.