ATP-SENSITIVE K-MUSCLE CELLS( CHANNELS IN PANCREATIC, CARDIAC, AND VASCULAR SMOOTH)

ATP-sensitive K+ (K-ATP) channels are therapeutic targets for several diseases, including angina, hypertension, and diabetes. This is becaus e stimulation of K-ATP channels is thought to produce vasorelaxation a nd myocardial protection against ischemia, whereas inhibition facilita tes insulin secretion. It is well known that native K-ATP channels are inhibited by ATP and sulfonylurea (SU) compounds and stimulated by nu cleotide diphosphates and K+ channel-opening drugs (KCOs). Although th ese characteristics can be shared with K-ATP channels in different tis sues, differences in properties among pancreatic, cardiac, and vascula r 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 understandi ng of K-ATP channels. For example, native K-ATP channels appear to be a complex of a regulatory protein containing the SU-binding site [sulf onylurea receptor (SUR)] and an inward-rectifying K+ channel (K-ir) se rving as a pore-forming subunit. Three isoforms of SUR (SUR1, SUR2A, a nd SUR2B) have been cloned and found to have two nucleotide-binding fo lds (NBFs). It seems that these NBFs play an essential role in conferr ing the MgADP and KCO sensitivity to the channel, whereas the K-ir cha nnel subunit itself possesses the ATP-sensing mechanism as an intrinsi c 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 (SUR2 A/ K(ir)6.2, cardiac type), and K(ir)6.1 with SUR2B (SUR2B/K(ir)6.1, V SM type) [i.e., (SUR/K(ir)6.x)(4)]. It remains to be determined what a re the molecular connections between the SUR and K-ir subunits that en able this unique complex to work as a functional K-ATP channel.