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J. Biol. Chem., Vol. 282, Issue 5, 3347-3356, February 2, 2007

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Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner^*

Annette Hambrock¹, Claudia Bernardo de Oliveira Franz, Sabrina Hiller, Almut Grenz, Stefanie Ackermann, Dorothea U. Schulze, Gisela Drews, and Hartmut Osswald

From the Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany and the Institute of Pharmacy, University of Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Germany

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_IR6.2 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 -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.

Received for publication, August 28, 2006 , and in revised form, November 27, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant HA2711/2-1 (to A. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-7071-2978261; Fax: 49-7071-294942; E-mail: annette.hambrock{at}uni-tuebingen.de.

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