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 -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.Sulfonylurea receptors (SURs) 2 are members of the ATPbinding cassette protein family (subfamily C). SURs are known to be the important regulatory subunits of ATP-sensitive K ϩ channels (K ATP channels). These channels are heteromeric complexes composed of four SUR subunits that surround a central pore formed by four subunits from the K IR 6.x family. K ATP channels found in various tissues exhibit distinct physiological and pharmacological properties because of the combination of different subunit isoforms (reviewed in Ref. 1). In addition to two nucleotide-binding domains, SUR possesses binding sites for synthetic K ATP channel modulators. The binding sites for blockers and openers are different, but they are linked via complex allosteric interactions (2, 3).Because of their nucleotide sensitivity, K ATP channels couple the energy metabolism of a cell to the membrane potential. This is important in the pancreatic -cell, in which closure of K ATP channels triggers insulin secretion via membrane depolarization in response to changes in blood glucose levels (4 -6). K ATP channel-blocking drugs such as the sulfonylureas and the glinides can promote insulin secretion and are used in the treatment of diabetes type 2. Insulin secretion is also modulated and amplified by other pathways...
Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of the pancreatic ATP-sensitive K ϩ 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 -cells or -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 -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.Sulfonylurea receptors (SUR) are members of the ATPbinding cassette protein family and form important regulatory subunits of ATP-sensitive K ϩ channels (K ATP channels). These channels are heterotetrameric complexes formed by SUR and the pore-forming Kir6.x subunit. Different combinations of these subunits (SUR1, SUR2A, or SUR2B and Kir6.1 or Kir6.2) form channels in various tissues with distinct pharmacological and electrophysiological properties. SUR2 is encoded by a different gene than SUR1. Alternative splicing of the SUR2 gene leads to expression of either SUR2A, predominantly found in heart and skeletal muscle, or SUR2B, typically occurring in smooth vascular muscle (Gribble and Reimann, 2003). To some extent, SUR1 and SUR2 show inverse pharmacological profiles; SUR1 exhibits high affinity for several sulfonylureas but low affinity for most K ATP channel openers, whereas SUR2 shows lower affinity for sulfonylureas and high affinity for openers (Schwanstecher et al., 1998;Hambrock et al., 2002).In the pancreatic -cell, K ATP channels (constituted by SUR1 and Kir6.2) are essential for triggering insulin secretion via membrane depolarization. High blood glucose concentrations lead to an elevated ATP/ADP ratio and result in clo...
Apoptosis of pancreatic -cells is an important factor in the pathophysiology of diabetes. Previously, we have shown that the "phytoestrogen" resveratrol can induce -cell apoptosis dependent on the expression of sulfonylurea receptor (SUR) 1, the regulatory subunit of pancreatic ATP-sensitive K ؉ channels. Here, we investigate whether 17-estradiol also influences -cell apoptosis in a SUR1-dependent manner. Therefore, islets from wild type or SUR1 knock-out mice, clonal -cells, or HEK293 cells expressing different SUR forms were treated with 17-estradiol or estrone. Different apoptotic parameters were determined and estrogen binding to SUR was analyzed. In murine islets, 17-estradiol treatment resulted in significant apoptotic changes, which in their nature (either apoptotic or anti-apoptotic) were dependent on the age of the animal. These effects were not observed in SUR1 knock-out mice. Furthermore, 17-estradiol, which specifically binds to SUR, induced enhanced apoptosis in SUR1-expressing HEK293 cells and clonal -cells, whereas apoptosis in recombinant cells expressing SUR2A or SUR2B (cardiac or vascular SUR-isoforms) or sham-transfected control cells was significantly lower. The apoptotic potency of 17-estradiol was much higher than that of resveratrol or estrone. SUR1-specific 17-estradiol-induced apoptosis was either abolished by the mutation M1289T in transmembrane helix 17 of SUR1 or clearly enhanced by two mutations in nucleotide binding fold 2 (R1379C, R1379L). In conclusion, 17-estradiol treatment modulates -cell apoptosis under specific involvement of SUR1 in an age-dependent manner. 17-Estradiol-induced apoptosis can be influenced by certain SUR1 mutations. These findings may contribute to the understanding of pathophysiological changes in -cell mass and could, for instance, provide interesting aspects concerning the etiology of gestational diabetes. Sulfonylurea receptors (SURs)2 are known to be the regulatory subunits of ATP-sensitive potassium channels (K ATP channels). These channels act as metabolic sensors due to their nucleotide sensitivity and play a key role in important cellular processes like, for instance, the triggering of insulin secretion. SURs regulate K ATP channel activity by binding of (Mg)ATP and/or (Mg)ADP to their nucleotide binding folds or by binding of synthetic K ATP channel modulators to different sites at SUR (1, 2).By analysis of several apoptotic parameters, we have previously shown that SUR ligands that act as K ATP channel blockers such as the synthetic insulinotropic sulfonylurea glibenclamide or the "phytoestrogen" trans-resveratrol can induce apoptotic cell death specifically depending on SUR1, the SUR isoform present in the pancreatic K ATP channel (3, 4). Enhanced apoptosis induced by these substances is not mediated by the electrical activity of K ATP channels as it is also observed in recombinant SUR1-expressing cells in the absence of the pore forming pancreatic channel subunit Kir6.2. These findings point to an additional function of SUR apart f...
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