Roles of ATP-Sensitive K~+ Channels as Metabolic Sensors: Studies of Kir6..x Null Mice

摘要

ATP-sensitive K~+ channels (K_(ATP) channels) are present in various tissues, including pancreatic β-cells, heart, skeletal muscles, vascular smooth muscles, and brain. K_(ATP) channels are hetero-octameric proteins composed of inwardly rectifying K~+ channel (Kir6..x) and sulfonyl-urea receptor (SUR) subunits. Different combinations of Kir6.x and SUR subunits comprise K_(ATP) channels with distinct electrophysiological and pharmacological properties. Recent studies of genetically engineered mice have provided insight into the physiological and patho-physiological roles of Kir6.x-containing K_(ATP) channels. Analysis of Kir6.2 null mice has shown that Kir6.2/SUR1 channels in pancreatic β-cells and the hypothalamus are essential in glucose-induced insulin secretion and hypo-glycemia-induced glucagon secretion, respectively, and that Kir6.2/SUR2 channels are involved in glucose uptake in skeletal muscles. Kir6.2-containing K_(ATP) channels in brain also are involved in protection from hypoxia-induced generalized seizure. In cardiovascular tissues, Kir6.1-containing K_(ATP) channels are involved in regulation of vascular tonus. In addition, the Kir6.1 null mouse is a model of Prinzmetal angina in humans. Our studies of Kir6.2 null and Kir6.1 null mice reveal that K_(ATP) channels are critical metabolic sensors in acute metabolic changes, including hyperglycemia, hypoglyce-mia, ischemia, and hypoxia.