Human KATP channelopathies: diseases of metabolic homeostasis

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 + (K ATP ) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. K ATP 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, K ATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in K ATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in K ATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, K ATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). K ATP 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 K ATP 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 K ATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy.