Cardiac ATP-sensitive K⁺ channels: Regulation by intracellular nucleotides and K⁺ channel-opening drugs

ATP-sensitive K⁺ (K(ATP)) channels are present at high density in membranes of cardiac cells where they regulate cardiac function during cellular metabolic impairment. K(ATP) channels have been implicated in the shortening of the action potential duration and the cellular loss of K⁺ that occurs during metabolic inhibition. K(ATP) channels have been associated with the cardioprotective mechanism of ischemia-related preconditioning. Intracellular ATP (ATP(i)) is the main regulator of K(ATP) channels. ATP(i) has two functions: 1) to close the channel (ligand function) and 2) in the presence of Mg²⁺, to maintain the activity of K(ATP) channels (presumably through an enzymatic reaction). K(ATP) channel activity is modulated by intracellular nucleoside diphosphates that antagonize the ATP(i)-induced inhibition of channel opening or induce K(ATP) channels to open. How nucleotides will affect K(ATP) channels depends on the state of the channel. K⁺ channel-opening drugs are pharmacological agents that enhance K(ATP) channel activity through different mechanisms and have great potential in the management of cardiovascular conditions. K(ATP) channel activity is also modulated by neurohormones. Adenosine, through the activation of a GTP- binding protein, antagonizes the ATP(i)-induced channel closure. Understanding the molecular mechanisms that underlie K(ATP) channel regulation should prove essential to further define the function of K(ATP) channels and to elucidate the pharmacological regulation of this channel protein. Since the molecular structure of the K(ATP) channel has now become available, it is anticipated that major progress in the K(ATP) channel field will be achieved.