Resveratrol binds to the sulfonylurea receptor (SUR) and induces apoptosis in a SUR subtype-specific manner.
Sulfonylurea receptors (SURs) constitute the regulatory subunits of ATP-sensitive K+ channels (K(ATP) channels). SUR binds nucleotides and synthetic K(ATP) channel modulators, e.g. the antidiabetic sulfonylurea glibenclamide, which acts as a channel blocker. However, knowledge about naturally occurring ligands of SUR is very limited. In this study, we show that the plant phenolic compound trans-resveratrol can bind to SUR and displace binding of glibenclamide. Electrophysiological measurements revealed that resveratrol is a blocker of pancreatic SUR1/K(IR)6.2 K(ATP) channels. We further demonstrate that, like glibenclamide, resveratrol induces enhanced apoptosis. This was shown by analyzing different apoptotic parameters (cell detachment, nuclear condensation and fragmentation, and activities of different caspase enzymes). The observed apoptotic effect was specific to cells expressing the SUR1 isoform and was not mediated by the electrical activity of K(ATP) channels, as it was observed in human embryonic kidney 293 cells expressing SUR1 alone. Enhanced susceptibility to resveratrol was not observed in pancreatic beta-cells from SUR1 knock-out mice or in cells expressing the isoform SUR2A or SUR2B or the mutant SUR1(M1289T). Resveratrol was much more potent than glibenclamide in inducing SUR1-specific apoptosis. Treatment with etoposide, a classical inducer of apoptosis, did not result in SUR isoform-specific apoptosis. In conclusion, resveratrol is a natural SUR ligand that can induce apoptosis in a SUR isoform-specific manner. Considering the tissue-specific expression patterns of SUR isoforms and the possible effects of SUR mutations on susceptibility to apoptosis, these observations could be important for diabetes and/or cancer research.
Hambrock
Annette
A
Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany. annette.hambrock@uni-tuebingen.de
de Oliveira Franz
Claudia Bernardo
CB
Hiller
Sabrina
S
Grenz
Almut
A
Ackermann
Stefanie
S
Schulze
Dorothea U
DU
Drews
Gisela
G
Osswald
Hartmut
H
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007668:Kidney; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015221:Potassium Channels / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011955:Receptors, Drug / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D064233:Sulfonylurea Receptors; D014162:Transfection
C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; C577511:Abcc9 protein, mouse; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D013267:Stilbenes; D064233:Sulfonylurea Receptors; D005047:Etoposide; D020169:Caspases; D000077185:Resveratrol