| First Author | Manna PT | Year | 2015 |
| Journal | Biochem J | Volume | 466 |
| Issue | 3 | Pages | 537-46 |
| PubMed ID | 25562606 | Mgi Jnum | J:220722 |
| Mgi Id | MGI:5635977 | Doi | 10.1042/BJ20140747 |
| Citation | Manna PT, et al. (2015) TRPM2-mediated intracellular Zn2+ release triggers pancreatic beta-cell death. Biochem J 466(3):537-46 |
| abstractText | Reactive oxygen species (ROS) can cause pancreatic beta-cell death by activating transient receptor potential (melastatin) 2 (TRPM2) channels. Cell death has been attributed to the ability of these channels to raise cytosolic Ca2+. Recent studies however revealed that TRPM2 channels can also conduct Zn2+, but the physiological relevance of this property is enigmatic. Given that Zn2+ is cytotoxic, we asked whether TRPM2 channels can permeate sufficient Zn2+ to affect cell viability. To address this, we used the insulin secreting (INS1) beta-cell line, human embryonic kidney (HEK)-293 cells transfected with TRPM2 and pancreatic islets. H2O2 activation of TRPM2 channels increases the cytosolic levels of both Ca2+ and Zn2+ and causes apoptotic cell death. Interestingly, chelation of Zn2+ alone was sufficient to prevent beta-cell death. The source of the cytotoxic Zn2+ is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn2+ release. Zn2+ release is potentiated by extracellular Ca2+ entry, indicating that Ca2+-induced Zn2+ release leads to apoptosis. Knockout of TRPM2 channels protects mice from beta-cell death and hyperglycaemia induced by multiple low-dose streptozotocin (STZ; MLDS) administration. These results argue that TRPM2-mediated, Ca2+-potentiated Zn2+ release underlies ROS-induced beta-cell death and Zn2+, rather than Ca2+, plays a primary role in apoptosis. |
