K _ATP Channels and Cardiovascular Disease

Abstract

ATP-sensitive potassium (KATP ) channels were first discovered in the heart 30 years ago1. Reconstitution of KATP channel activity by coexpression of members of the pore-forming inward rectifier gene family (Kir6.1, KCNJ8, and Kir6.2 KCNJ11) with sulfonylurea receptors (SUR1, ABCC8, and SUR2, ABCC9) of the ABCC protein sub-family, has led to the elucidation of many details of channel gating and pore properties. In addition, the essential roles of Kir6.x and SURx subunits in generating cardiac and vascular KATP2 and the detrimental consequences of genetic deletions or mutations in mice have been recognised3. However, despite this extensive body of knowledge, there has been a paucity of defined roles of KATP subunits in human cardiovascular diseases, although there are reports of association of a single Kir6.1 variant with the J-wave syndrome in the electrocardiogram, and two isolated studies have reported association of loss of function mutations in SUR2 with atrial fibrillation and heart failure. Two new studies convincingly demonstrate that mutations in the SUR2 gene are associated with Cantu syndrome, a complex multi-organ disorder characterized by hypertrichosis, craniofacial dysmorphology, osteochondrodysplasia, patent ductus arteriosus, cardiomegaly, pericardial effusion, and lymphoedema. As we discuss, this realization of previously unconsidered consequences provides significant insight into the roles of the KATP channel in the cardiovascular system and suggests novel therapeutic possibilities.

Cardiac ion channels

“…86 Recently, mutations in SUR2 have been linked to Cantu syndrome, characterized by multi-organ developmental abnormalities. 88 These mutations are considered gain-of-function with regard to K ATP , since they result in channels with reduced sensitivity to ATP inhibition. In mice, ablation and gain-of-function of Kir6.2 results mainly in metabolic deficiencies.…”

Diazoxide Cardioprotection Is Independent of Adenosine Triphosphate-Sensitive Potassium Channel Kir 6.1 Subunit in Response to Stress

“…The Kir6.1 subunit combines with subunit SUR2B to form the predominant K ATP channel in vascular smooth muscle (27). Mice lacking Kir6.1 demonstrate a loss of K ATP function in vascular smooth muscle and can exhibit sudden death due to arrhythmias (heart block) secondary to coronary spasm and ischemia (20).…”

Genetic Basis of Brugada Syndrome

“…Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages [38]. Pathogenic mutations in this gene have been associated to SIDS, J-wave syndromes and BrS (Figure 2).…”