TRUNCATION OF KIR6.2 PRODUCES ATP-SENSITIVE K+ CHANNELS IN THE ABSENCE OF THE SULFONYLUREA RECEPTOR

ATP-sensitive potassium channels (K-ATP channels) couple cell metaboli sm to electrical activity and are important in the physiology and path ophysiology of many tissues(1). In pancreatic beta-cells, K-ATP channe ls Link changes in blood glucose concentration to insulin secretion(2) . They are also the target for clinically important drugs such as sulp honylureas, which stimulate secretion, and the K+ channel opener diazo xide, which inhibits insulin release(3,4). Metabolic regulation of K-A TP channels is mediated by changes in intracellular ATP and Mg-ADP lev els, which inhibit and activate the channel, respectively(2). The beta -cell K-ATP channel is a complex of two proteins(5,6): an inward-recti fier K+ channel subunit, Kir6.2, and the sulphonylurea receptor, SUR1. We show here that the primary site at which ATP acts to mediate K-ATP channel inhibition is located on Kir6.2, and that SUR1 is required fo r sensitivity to sulphonylureas and diazoxide and for activation by Mg -ADP.