title: Epac2: a sulfonylurea receptor?
abstract: Sulfonylureas are widely used oral drugs in the treatment of diabetes mellitus. They function by the inhibition of ATP-sensitive K+ channels in pancreatic β-cells, which are thus considered the 'classical' sulfonylurea receptor. Next to the ATP-sensitive K+ channels, additional sulfonylurea-interacting proteins were identified, which might contribute to the physiological effects of this drug family. Most recently, Epac2 (exchange protein directly activated by cAMP 2) was added to the list of sulfonylurea receptors. However, this finding caused controversy in the literature. The critical discussion of the present paper comes to the conclusion that sulfonylureas are not able to activate Epac2 directly and are unlikely to bind to Epac2. Increased blood glucose levels after food intake result in the secretion of insulin from pancreatic β-cells. Glucose levels are detected 'indirectly' by β-cells: owing to increased glycolysis rates, the ratio of cellular ATP/ADP increases and causes the closure of ATP-sensitive K+ channels. In consequence, cells depolarize and voltage-dependent Ca2+ channels open to cause an increase in the cellular Ca2+ concentration. Finally, Ca2+ induces the fusion of insulin-containing granules with the plasma membrane. Sulfonylureas, such as tolbutamide, glibenclamide or acetohexamide, form a class of orally applicable drugs used in the treatment of non-insulin-dependent diabetes mellitus.
authors.affiliation: Department of Molecular Cancer Research, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. h.rehmann@umcutrecht.nl
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D011955:Receptors, Drug / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013453:Sulfonylurea Compounds / Q000378:metabolism / Q000494:pharmacology; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; D020662:Guanine Nucleotide Exchange Factors; D024661:Potassium Channels, Inwardly Rectifying; C442864:RAPGEF4 protein, human; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors