Li, X, Yang, W and Jiang, L-H orcid.org/0000-0001-6398-0411 (2017) Alteration in intracellular Zn2+ homeostasis as a result of TRPM2 channel activation contributes to ROS-induced hippocampal neuronal death. Frontiers in Molecular Neuroscience, 10. 414. ISSN 1662-5099
Abstract
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 Zn2+ 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 Zn2+ homeostasis in mouse hippocampal neurons. Exposure of neurons to 30-300 M H2O2 for 2-24 hr 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 Zn2+ selective chelator. Single cell imaging demonstrated that H2O2 evoked a prominent increase in the intracellular Zn2+ concentration, which was completely prevented by TPEN as well as TRPM2-KO and inhibition of the TRPM2 channel. Furthermore, H2O2 induced lysosomal Zn2+ release and lysosomal dysfunction, and subsequent mitochondrial Zn2+ 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 Zn2+ homeostasis as a result of activation of the TRPM2 channel contributes to ROS-induced hippocampal neuronal death.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | Copyright © 2017 Li, Yang and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
Keywords: | TRPM2 channel, hippocampal neuronal death, ROS, Zn2+ homeostasis, lysosomal dysfunction, Mitochondrial dysfunction |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number Alzheimer's Research UK ART/PPG2009A/2 |
Depositing User: | Symplectic Publications |
Date Deposited: | 06 Dec 2017 09:38 |
Last Modified: | 23 Jun 2023 22:40 |
Status: | Published |
Publisher: | Frontiers Media |
Identification Number: | 10.3389/fnmol.2017.00414 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:124769 |