Effect of MgATP on pinacidil-induced displacement of glibenclamide from the sulphonylurea receptor in a pancreatic beta-cell line and rat cerebral cortex.
1. The effects of blockers and openers of K+ channels on binding of [3H]-glibenclamide to microsomes obtained from a pancreatic beta-cell line (HIT-T15) or rat cerebral cortex were examined. 2. The blockers quinine, chlorpromazine and thiopentone and the openers cromakalim [(+/- ) 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1- pyrrolidyl)-2H-benzo[b]pyran-3-ol] and minoxidil sulphate did not significantly interact with the sulphonylurea receptor of HIT-cells both at phosphorylating (presence of MgATP) and dephosphorylating (absence of MgATP) conditions. 3. In the absence of MgATP, pinacidil (200-500 microM) did not significantly displace [3H]-glibenclamide binding to microsomes from HIT-cells. The displacement of [3H]-glibenclamide binding was strongly enhanced by MgATP and was due to a decrease in the number of high affinity binding sites for glibenclamide. 4. MgATP enhanced pinacidil-induced inhibition of [3H]-glibenclamide binding to microsomes from rat cerebral cortex. 5. The effect of MgATP on pinacidil-induced inhibition of [3H]-glibenclamide binding was maintained after solubilization of the membranes from HIT-cells or rat cerebral cortex. 6. It is concluded that the sulphonylurea receptor is regulated not only by sulphonylureas but also by the K+ channel openers, diazoxide and pinacidil, and by protein phosphorylation. The binding sites for sulphonylureas and these K+ channel openers are not identical, but appear to be located at a single protein or at tightly associated proteins.
Schwanstecher
M
M
Institute of Pharmacology and Toxicology, University of Göttingen, Germany.
Brandt
C
C
Behrends
S
S
Schaupp
U
U
Panten
U
U
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005905:Glyburide / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000187:drug effects*; D064233:Sulfonylurea Receptors
D018528:ATP-Binding Cassette Transporters; D006146:Guanidines; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D020110:Pinacidil; D000255:Adenosine Triphosphate; D005905:Glyburide