Function, regulation, pharmacology, and molecular structure of ATP-sensitive K+ channels in the cardiovascular system.

Abstract

ATP-sensitive K+ (K[ATP]) channels are inhibited by intracellular ATP and activated by intracellular nucleoside diphosphates, and thus provide a link between cellular metabolism and excitability. K(ATP) channels are widely distributed in various tissues and may be associated with diverse cellular functions. In the heart, the K(ATP) channel appears to be activated during ischemic or hypoxic conditions and may be responsible for the increase of K+ efflux and shortening of the action potential duration. Therefore, opening of this channel may result in cardioprotective as well as proarrhythmic effects. In the vascular smooth muscle, the K(ATP) channel is believed to mediate the relaxation of vascular tone. Thus, K(ATP) channels play important regulatory roles in the cardiovascular system. Furthermore, K(ATP) channels are the targets of two important classes of drugs, i.e., the antidiabetic sulfonylureas, which block the channels, and a series of vasorelaxants called "K+ channel openers," which tend to maintain the channels in an open conformation. Recently, the molecular structure of K(ATP) channels has been clarified. The K(ATP) channel in pancreatic beta-cells is a complex composed of at least two subunits, a member of inwardly rectifying K+ channels and a sulfonylurea receptor. Subsequently, two additional homologs of the sulfonylurea receptor, which form cardiac and smooth muscle type K(ATP) channels, respectively, have been reported. Further works are now in progress to understand the molecular mechanisms of K(ATP) channel function.