Tissue specificity of sulfonylureas: studies on cloned cardiac and beta-cell K(ATP) channels.
Sulfonylureas stimulate insulin secretion from pancreatic beta-cells by 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 subunits (SUR1 and SUR2A, respectively). We examined the mechanism underlying the tissue specificity of the sulfonylureas tolbutamide and glibenclamide, and the benzamido-derivative meglitinide, using cloned beta-cell (Kir6.2/SUR1) and cardiac (Kir6.2/SUR2A) K(ATP) channels expressed in Xenopus oocytes. Tolbutamide inhibited Kir6.2/SUR1 (Ki approximately 5 micromol/l), but not Kir6.2/SUR2A, currents with high affinity. Meglitinide produced high-affinity inhibition of both Kir6.2/SUR1 and Kir6.2/SUR2A currents (Kis approximately 0.3 micromol/l and approximately 0.5 micromol/l, respectively). Glibenclamide also blocked Kir6.2/SUR1 and Kir6.2/SUR2A currents with high affinity (Kis approximately 4 nmol/l and approximately 27 nmol/l, respectively); however, only for cardiac-type K(ATP) channels was this block reversible. Physiological concentrations of MgADP (100 micromol/l) enhanced glibenclamide inhibition of Kir6.2/SUR1 currents but reduced that of Kir6.2/SUR2A currents. The results suggest that SUR1 may possess separate high-affinity binding sites for sulfonylurea and benzamido groups. SUR2A, however, either does not possess a binding site for the sulfonylurea group or is unable to translate the binding at this site into channel inhibition. Although MgADP reduces the inhibitory effect of glibenclamide on cardiac-type K(ATP) channels, drugs that bind to the common benzamido site have the potential to cause side effects on the heart.
Gribble
F M
FM
University Laboratory of Physiology, Oxford, England, UK.
Tucker
S J
SJ
Seino
S
S
Ashcroft
F M
FM
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D003001:Cloning, Molecular; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D006321:Heart / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D009865:Oocytes; D009928:Organ Specificity; D015221:Potassium Channels / Q000096:biosynthesis / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D011955:Receptors, Drug / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D064233:Sulfonylurea Receptors; D014044:Tolbutamide / Q000494:pharmacology*; D014982:Xenopus laevis
D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat; C577511:Abcc9 protein, mouse; D001549:Benzamides; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; C030516:meglitinide; D014044:Tolbutamide; D005905:Glyburide