The role of ATP-sensitive potassium channels in cellular function and protection in the cardiovascular system

Abstract

ATP-sensitive potassium channels (K(ATP)) are widely distributed and present in a number of tissues including muscle, pancreatic beta cells and the brain. Their activity is regulated by adenine nucleotides, characteristically being activated by falling ATP and rising ADP levels. Thus, they link cellular metabolism with membrane excitability. Recent studies using genetically modified mice and genomic studies in patients have implicated K(ATP) channels in a number of physiological and pathological processes. In this review, we focus on their role in cellular function and protection particularly in the cardiovascular system.

Keywords: ATP-sensitive potassium channel; cardiac myocyte; pathophysiology; physiology; smooth muscle.

Figure 1

Molecular basis of the K_ATP channel. (A) K_ATP channels are composed of K_IR6x (6.1 or 6.2) and SUR subunits. A tetrameric arrangement of K_IR6x subunits forms the channel pore, with each subunit comprised of two transmembrane domains (M1 and M2) with intracellular N- and C-terminus and a pore-forming H5 region with the K+ selectivity sequence. SUR has 17 transmembrane segments split into three domains, TMD0-2. TMD0 and L0 interact and modulate gating of K_IR6. TMD1-2 and the C-terminus contain the NBD1 and NBD2 with Walker A and B motifs where ATP binding and hydrolysis take place. SUR is also the pharmacological target of K_CO compounds such as pinacidil and diazoxide, and sulphonylurea drugs, such as glibenclamide and tolbutamide. The mature K_ATP channel is a hetero-octameric structure of K_IR6x and SURx subunits. (B) Tissue-specific composition of K_ATP channels in the cardiovascular system.

Figure 2

Functional roles of K_IR6.1 and K_IR6.2 in the cardiovascular system. (A) K_ATP channels comprising K_IR6.1 in vascular smooth muscle (VSM) cells regulate vascular tone by controlling the membrane potential and subsequently the influx of Ca²⁺ through L-type voltage-dependent Ca²⁺ channels. K_ATP channel activity in VSM can be modulated by the PKC (inhibitory) and PKA (activation) signalling pathways and metabolic stress such as hypoxia and ischaemia. (B) K_IR6.2-containing K_ATP channels are predominant in cardiomyocytes, where they are involved in AP repolarization. Activation of K_ATP by PKC or metabolic insults such as ischaemia and/or hypoxia leads to shortening of AP duration, decreased influx of Ca²⁺ and reduced contractility, thus preventing Ca²⁺ overload and ATP preservation.