Cardiac K_ATP channels in health and disease

ATP-sensitive potassium (K_ATP) channels are evolutionarily conserved plasma-membrane protein complexes, widely represented in tissue beds with high metabolic activity. There, they are formed through physical association of the inwardly rectifying potassium channel pore, most typically Kir6.2, and the regulatory sulfonylurea receptor subunit, an ATP-binding cassette protein. Energetic signals, received via tight integration with cellular metabolic pathways, are processed by the sulfonylurea receptor subunit that in turn gates the nucleotide sensitivity of the channel pore thereby controlling membrane potential dependent cellular functions. Recent findings, elicited from genetic disruption of channel proteins, have established in vivo the requirement of intact K_ATP channels in the proper function of cardiac muscle under stress. In the heart, where K_ATP channels were originally discovered, channel ablation compromises cardioprotection under ischemic insult. New data implicate the requirement of intact K_ATP channels for the cardiac adaptive response to acute stress. K_ATP channels have been further implicated in the adaptive cardiac response to chronic (patho)physiologic hemodynamic load, with K_ATP channel deficiency affecting structural remodeling, rendering the heart vulnerable to calcium-dependent maladaptation and predisposing to heart failure. These findings are underscored by the identification in humans that defective K _ATP channels induced by mutations in ABCC9, the gene encoding the cardiac sulfonylurea receptor subunit, confer susceptibility to dilated cardiomyopathy. Thus, in parallel with the developed understanding of the molecular identity and mode of action of K_ATP channels since their discovery, there is now an expanded understanding of their critical significance in the cardiac stress response in health and disease.