Hambrock Annette, de Oliveira Franz Claudia Bernardo, Hiller Sabrina, Grenz Almut, Ackermann Stefanie, Schulze Dorothea U, Drews Gisela, Osswald Hartmut
Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany.
J Biol Chem. 2007 Feb 2;282(5):3347-56. doi: 10.1074/jbc.M608216200. Epub 2006 Nov 30.
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.
磺脲类受体（SURs）构成了ATP敏感性钾通道（K(ATP)通道）的调节亚基。SUR能结合核苷酸和合成的K(ATP)通道调节剂，例如抗糖尿病药物磺脲类的格列本脲，它作为一种通道阻滞剂发挥作用。然而，关于SUR天然存在的配体的了解非常有限。在本研究中，我们表明植物酚类化合物反式白藜芦醇能够结合SUR并取代格列本脲的结合。电生理测量结果显示白藜芦醇是胰腺SUR1/K(IR)6.2 K(ATP)通道的阻滞剂。我们进一步证明，与格列本脲一样，白藜芦醇能诱导增强的细胞凋亡。这是通过分析不同的凋亡参数（细胞脱离、核浓缩和碎片化以及不同半胱天冬酶的活性）得以证实的。观察到的凋亡效应对于表达SUR1亚型的细胞具有特异性，并且不是由K(ATP)通道的电活动介导的，因为在单独表达SUR1的人胚肾293细胞中也观察到了这种效应。在来自SUR1基因敲除小鼠的胰腺β细胞中，或者在表达SUR2A或SUR2B亚型或突变型SUR1(M1289T)的细胞中，未观察到对白藜芦醇的易感性增强。在诱导SUR1特异性细胞凋亡方面，白藜芦醇比格列本脲的效力要强得多。用拓扑替康（一种经典的细胞凋亡诱导剂）处理不会导致SUR亚型特异性细胞凋亡。总之，白藜芦醇是一种天然的SUR配体，能够以SUR亚型特异性的方式诱导细胞凋亡。考虑到SUR亚型的组织特异性表达模式以及SUR突变对细胞凋亡易感性的可能影响，这些观察结果对于糖尿病和/或癌症研究可能具有重要意义。
