ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells

ATP-sensitive K+ (K-ATP) channels are therapeutic targets for several diseases, including angina, hypertension, and diabetes. This is because stimulation of K-ATP channels is thought to produce vasorelaxation and myocardial protection against ischemia, whereas inhibition facilitates insulin secretion. It is well known that native K-ATP channels are inhibited by ATP and sulfonylurea (SU) compounds and stimulated by nucleotide diphosphates and K+ channel-opening drugs (KCOs). Although these characteristics can be shared with K-ATP channels in different tissues, differences in properties among pancreatic, cardiac, and vascular smooth muscle (VSM) cells do exist in terms of the actions produced by such regulators. Recent molecular biology and electrophysiological studies have provided useful information toward the better understanding of K-ATP channels. For example, native K-ATP channels appear to be a complex of a regulatory protein containing the SU-binding site [sulfonylurea receptor (SUR)] and an inward-rectifying K+ channel (K-ir) serving as a pore-forming subunit. Three isoforms of SUR (SUR1, SUR2A, and SUR2B) have been cloned and found to have two nucleotide-binding folds (NBFs). It seems that these NBFs play an essential role in conferring the MgADP and KCO sensitivity to the channel, whereas the K-ir channel subunit itself possesses the ATP-sensing mechanism as an intrinsic property. The molecular structure of K-ATP channels is thought to be a heteromultimeric (tetrameric) assembly of these complexes: K(ir)6.2 with SUR1 (SUR1/K(ir)6.2, pancreatic type), K(ir)6.2 with SUR2A (SUR2A/ K(ir)6.2, cardiac type), and K(ir)6.1 with SUR2B (SUR2B/K(ir)6.1, VSM type) [i.e., (SUR/K(ir)6.x)(4)]. It remains to be determined what are the molecular connections between the SUR and K-ir subunits that enable this unique complex to work as a functional K-ATP channel.