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

ATP-sensitiveK⁺(K_ATP) channels are therapeutictargets for several diseases, including angina, hypertension, anddiabetes. This is because stimulation ofK_ATP channels is thought toproduce vasorelaxation and myocardial protection against ischemia,whereas inhibition facilitates insulin secretion. It is well known that native K_ATP channels are inhibitedby ATP and sulfonylurea (SU) compounds and stimulated by nucleotidediphosphates and K⁺channel-opening drugs (KCOs). Although these characteristics can beshared with K_ATP channels indifferent tissues, differences in properties among pancreatic, cardiac,and vascular smooth muscle (VSM) cells do exist in terms of the actionsproduced by such regulators. Recent molecular biology andelectrophysiological studies have provided useful information towardthe better understanding of K_ATPchannels. For example, native K_ATPchannels appear to be a complex of a regulatory protein containing theSU-binding site sulfonylurea receptor (SUR)] and aninward-rectifying K⁺ channel(K_ir) serving as a pore-formingsubunit. Three isoforms of SUR (SUR1, SUR2A, and SUR2B) have beencloned and found to have two nucleotide-binding folds (NBFs). It seemsthat these NBFs play an essential role in conferring the MgADP and KCOsensitivity to the channel, whereas theK_ir channel subunit itselfpossesses the ATP-sensing mechanism as an intrinsic property. Themolecular structure of K_ATPchannels is thought to be a heteromultimeric (tetrameric) assembly ofthese complexes: K_ir6.2 with SUR1(SUR1/K_ir6.2, pancreatic type),K_ir6.2 with SUR2A(SUR2A/K_ir6.2, cardiac type), andK_ir6.1 with SUR2B(SUR2B/K_ir6.1, VSM type)i.e.,(SUR/K_ir6.x)₄]. It remains to be determined what are the molecular connections betweenthe SUR and K_ir subunits thatenable this unique complex to work as a functionalK_ATP channel.