Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers

ATP-sensitive K+ (K-ATP) channels are inhibited by intracellular ATP (ATP(i)) 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. These channels are clearly heterogeneous. The cardiac K-ATP channel is the prototype of K-ATP channels possessing similar to 80 pS of single-channel conductance in the presence of similar to 150 mM extracellular K+ and opens spontaneously in the absence of ATP(i). A vascular K-ATP channel called a nucleoside diphosphate-dependent K+ (K-NDP) channel exhibits properties significantly different from those of the cardiac K-ATP channel. The K-NDP channel has the single-channel conductance of similar to 30-40 pS in the presence of similar to 150 mM extracellular K+, is closed in the absence of ATP,, and requires intracellular nucleoside di- or triphosphates, including ATP(i) to open. Nevertheless, K-ATP and K-NDP channels are both activated by K+ channel openers, including pinacidil and nicorandil, and inhibited by sulfonylurea derivatives such as glibenclamide. It recently was found that the cardiac K-ATP channel is composed of a sulfonylurea receptor (SUR)2A and a two-transmembrane-type K+ channel subunit Kir6.2, while the vascular KNDP channel may be the complex of SUR2B and Kir6.1. By precisely comparing the functional properties of the SUR2A/Kir6.2 and the SUR2B/Kir6.1 channels, we shall show that the single-channel characteristics and pharmacological properties of SUR/Kir6.0 channels are determined by Kir and SUR subunits. respectively, while responses to intracellular nucleotides are determined by both SUR and Kir subunits. (C) 1999 Elsevier Science Inc. All rights reserved.