| First Author | Li X | Year | 2017 |
| Journal | Front Mol Neurosci | Volume | 10 |
| Pages | 414 | PubMed ID | 29311807 |
| Mgi Jnum | J:311989 | Mgi Id | MGI:6782323 |
| Doi | 10.3389/fnmol.2017.00414 | Citation | Li X, et al. (2017) Alteration in Intracellular Zn(2+) Homeostasis as a Result of TRPM2 Channel Activation Contributes to ROS-Induced Hippocampal Neuronal Death. Front Mol Neurosci 10:414 |
| abstractText | Transient receptor potential melastatin-related 2 (TRPM2) channel, a molecular sensor for reactive oxygen species (ROS), plays an important role in cognitive dysfunction associated with post-ischemia brain damage thought to result from ROS-induced TRPM2-dependent neuronal death during reperfusion. Emerging evidence further suggests that an alteration in the Zn(2+) homeostasis is critical in ROS-induced TRPM2-dependent neuronal death. Here we applied genetic and pharmacological interventions to define the role of TRPM2 channel in ROS-induced neuronal death and explore the mechanisms contributing in the alteration in intracellular Zn(2+) homeostasis in mouse hippocampal neurons. Exposure of neurons to 30-300 muM H2O2 for 2-24 h caused concentration/duration-dependent neuronal death, which was significantly suppressed, but not completely prevented, by TRPM2-knockout (TRPM2-KO) and pharmacological inhibition of the TRPM2 channel. H2O2-induced neuronal death was also attenuated by treatment with TPEN acting as a Zn(2+) selective chelator. Single cell imaging demonstrated that H2O2 evoked a prominent increase in the intracellular Zn(2+) concentration, which was completely prevented by TPEN as well as TRPM2-KO and inhibition of the TRPM2 channel. Furthermore, H2O2 induced lysosomal Zn(2+) release and lysosomal dysfunction, and subsequent mitochondrial Zn(2+) accumulation that provokes mitochondrial dysfunction and ROS generation. These H2O2-induced lysosomal/mitochondrial effects were prevented by TRPM2-KO or TPEN. Taken together, our results provide evidence to show that a dynamic alteration in the intracellular Zn(2+) homeostasis as a result of activation of the TRPM2 channel contributes to ROS-induced hippocampal neuronal death. |
