Glibenclamide-Induced Apoptosis Is Specifically Enhanced by Expression of the Sulfonylurea Receptor Isoform SUR1 but Not by Expression of SUR2B or the Mutant SUR1(M1289T)

• Published in: The Journal of pharmacology and experimental therapeutics 2006-03, Vol.316 (3), p.1031-1037
• Main Authors: Hambrock, Annette, de Oliveira Franz, Claudia Bernardo, Hiller, Sabrina, Osswald, Hartmut
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; ATP-Binding Cassette Transporters - physiology; Caspase 3; Caspases - physiology; Cell Adhesion - drug effects; Cell Line; DNA Fragmentation - drug effects; Etoposide - pharmacology; Glyburide - pharmacology; Humans; Mutation; Potassium Channels - physiology; Potassium Channels, Inwardly Rectifying - physiology; Protein Isoforms; Receptors, Drug - physiology; Sulfonylurea Receptors
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.097501

Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of the pancreatic ATP-sensitive K + channel (K ATP channel), which is essential for triggering insulin secretion via membrane depolarization. Sulfonylureas, such as glibenclamide and tolbutamide, act as K ATP channel blockers and are widely used in diabetes treatment. These antidiabetic substances are known to induce apoptosis in pancreatic β-cells or β-cell lines under certain conditions. However, the precise molecular mechanisms of this sulfonylurea-induced apoptosis are still unidentified. To investigate the role of SUR in apoptosis induction, we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either SUR1, the smooth muscular isoform SUR2B, or the mutant SUR1(M1289T) at which a single amino acid in transmembrane helix 17 (TM17) was exchanged by the corresponding amino acid of SUR2. By analyzing cell detachment, nuclear condensation, DNA fragmentation, and caspase-3-like activity, we observed a SUR1-specific enhancement of glibenclamide-induced apoptosis that was not seen in SUR2B, SUR1(M1289T), or control cells. Coexpression with the pore-forming Kir6.2 subunit did not significantly alter the apoptotic effect of glibenclamide on SUR1 cells. In conclusion, expression of SUR1, but not of SUR2B or SUR1(M1289T), renders cells more susceptible to glibenclamide-induced apoptosis. Therefore, SUR1 as a pancreatic protein could be involved in specific variation of β-cell mass and might also contribute to the regulation of insulin secretion at this level. According to our results, TM17 is essentially involved in SUR1-mediated apoptosis. This effect does not require the presence of functional Kir6.2-containing K ATP channels, which points to additional, so far unknown functions of SUR.