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)

Abstract

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...

Suppression of KATP channel activity protects murine pancreatic β cells against oxidative stress

“…These observations are in agreement with reports that closure of K ATP channels augments the rate of apoptosis in β cells (65) and in HEK-293 cells expressing the β cell-specific K ATP channel subunit SUR1 (66). Importantly, the enhancement of the basal rate of apoptosis in Sur1 -/-cells did not cause significant deleterious effects in vivo, but was compatible with protection against STZ-induced -and thus ROS-mediated -diabetes.…”

Different sulfonylureas induce the apoptosis of proximal tubular epithelial cell differently via closing KATP channel

“…In addition, our results are consistent with previous observations that autophagy protects PTECs from injury and apoptosis (Dong et al 2015; Xu et al 2016). Other research indicates that increased cytosolic Ca 2+ levels regulated by K ATP channels play a role in impairing autophagy, which is associated with neurodegenerative disorders (Hambrock et al 2006). Altogether these studies brought an assumption that SUs could interfere with autophagy through their action on K ATP channels, which then play a part in SUs-induced apoptosis of PTECs.…”

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