Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Pflugers Arch. 2010 Jul;460(2):295-306. doi: 10.1007/s00424-009-0771-y. Epub 2009 Dec 24.
Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATP-sensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in KATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, KATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-at-large and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within KATP channel genes and the spectrum of genotype-phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy.
内向整流钾离子通道（Kir6.1/Kir6.2）和三磷酸腺苷（ATP）结合调节亚基（SUR1/SUR2A/SUR2B）的组装形成了 ATP 敏感性钾离子（KATP）通道异源多聚体，广泛分布于全身代谢活跃的组织中。KATP 通道是代谢门控生物传感器，作为分子变阻器，调节膜电位依赖性功能以适应细胞能量需求。在（病理）生理应激的适应性反应中至关重要，KATP 通道在葡萄糖调节到心脏保护等方面发挥着维持体内平衡的作用。因此，KATP 通道亚基的遗传变异与危及生命的人类疾病的病因有关。特别是，在胰岛素分泌紊乱（即先天性高胰岛素血症和新生儿糖尿病）中发现了 KATP 通道的致病性突变。此外，KATP 通道缺陷是发育迟缓、癫痫和新生儿糖尿病（DEND 综合征）三联征的基础。与机械和/或电心脏疾病相关的 KATP 通道病包括扩张型心肌病（伴室性心律失常；CMD1O）和肾上腺素能性心房颤动。常见的 Kir6.2 E23K 多态性与迟发性糖尿病有关，也是一般人群中心脏重构适应性不良和心力衰竭患者心肺运动应激表现异常的危险因素。KATP 通道基因内的总体突变频率和基因型-表型关系谱仍有待确定，而通过系统生物学方法预测通道功能缺陷的后果正变得越来越可行。因此，人类 KATP 通道病这一新兴领域的分子医学进展为有针对性的个体化筛查、早期诊断和针对性治疗提供了新的机会。
