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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 23, 2005; DOI: 10.1124/jpet.105.097501

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Annette Hambrock
Claudia Bernardo de Oliveira Franz
Sabrina Hiller
Hartmut Osswald
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Received for publication October 20, 2005.
Revised November 17, 2005.
Accepted for publication November 21, 2005.

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)

Annette Hambrock 1*, Claudia Bernardo de Oliveira Franz 1, Sabrina Hiller 1, Hartmut Osswald 1

1 University of Tuebingen, Department of Pharmacology and Toxicology

* Address correspondence to: E-mail: annette.hambrock{at}uni-tuebingen.de

Abstract

Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of the pancreatic ATP-sensitive K+ channel (KATP channel) which is essential for triggering insulin secretion via membrane depolarization. Sulfonylureas such as glibenclamide and tolbutamide act as KATP channel blockers and are widely used in diabetes treatment. These antidiabetic substances are known to induce apoptosis in pancreatic {beta}-cells or {beta}-cell lines under certain conditions. The precise molecular mechanisms of this sulfonylurea-induced apoptosis, however, are still unidentified. In order to investigate the role of SUR in apoptosis induction, we tested the effect of glibenclamide on recombinant HEK293 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. SUR1 as a pancreatic protein could therefore be involved in specific variation of {beta}-cell mass and might also contribute to 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 KATP channels, which points to additional, so far unknown functions of SUR.


Key words: ATP-binding cassette protein, ATP-sensitive potassium channel, apoptosis, glibenclamide, sulfonylurea, sulfonylurea receptor




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