TISSUE-SPECIFICITY OF SULFONYLUREAS - STUDIES ON CLONED CARDIAC AND BETA-CELL K-ATP CHANNELS

Sulfonylureas stimulate insulin secretion from pancreatic beta-cells b y closing ATP-sensitive K+ (K-ATP). The beta-cell and cardiac muscle K -ATP channels have recently been cloned and shown to possess a common pore-forming subunit (Kir6.2) but different sulfonylurea receptor subu nits (SUR1 and SUR2A, respectively). We examined the mechanism underly ing the tissue specificity of the sulfonylureas tolbutamide and gliben clamide, and the benzamido-derivative meglitinide, using cloned beta-c ell (Kir6.2/SUR1) and cardiac (Kir6.2/SUR2A) K-ATP channels expressed in Xenopus oocytes. Tolbutamide inhibited Kir6.2/SUR1 (K-i similar to 5 mu mol/l), but not Kir6.2/SUR2A, currents with high affinity. Meglit inide produced high-affinity inhibition of both Kir6.2/SUR1 and Kir6.2 /SUR2A currents (K(i)s similar to 0.3 mu mol/l and similar to 0.5 mu m ol/l, respectively). Glibenclamide also blocked Kir6.2/SUR1 and Kir6.2 /SUR2A currents with high affinity (K(i)s similar to 4 nmol/l and simi lar to 27 nmol/l, respectively); however, only for cardiac-type K-ATP channels was this block reversible. Physiological concentrations of Mg ADP (100 pmol/l) enhanced glibenclamide inhibition of Kir6.2/SUR1 curr ents but reduced that of Kir6.2/SUR2A currents. The results suggest th at SUR1 may possess separate high-affinity binding sites for sulfonylu rea and benzamido groups. SUR2A, however, either does not possess a bi nding site for the sulfonylurea group or is unable to translate the bi nding at this site into channel inhibition. Although MgADP reduces the inhibitory effect of glibenclamide on cardiac-type K-ATP channels, dr ags that bind to the common benzamido site have the potential to cause side effects on the heart.