Signalling mechanisms mediating Zn2+-induced TRPM2 channel activation and cell death in microglial cells
| Autor: | Joan A. Sim, Sharifah Alawieyah Syed Mortadza, Martin Stacey, Lin-Hua Jiang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
inorganic chemicals
0301 basic medicine MAPK/ERK pathway Programmed cell death Multidisciplinary Kinase Poly ADP ribose polymerase Biology Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Chelerythrine chemistry PARP inhibitor TRPM2 General Protein kinase C |
| Zdroj: | Mortadza, S S, Sim, J A, Stacey, M & Jiang, L H 2017, ' Signalling mechanisms mediating Zn 2+-induced TRPM2 channel activation and cell death in microglial cells ', Scientific Reports, vol. 7, 45032 . https://doi.org/10.1038/srep45032 |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep45032 |
| Popis: | Excessive Zn2+ causes brain damage via promoting ROS generation. Here we investigated the role of ROS-sensitive TRPM2 channel in H2O2/Zn2+-induced Ca2+ signalling and cell death in microglial cells. H2O2/Zn2+ induced concentration-dependent increases in cytosolic Ca2+ concentration ([Ca2+]c), which was inhibited by PJ34, a PARP inhibitor, and abolished by TRPM2 knockout (TRPM2-KO). Pathological concentrations of H2O2/Zn2+ induced substantial cell death that was inhibited by PJ34 and DPQ, PARP inhibitors, 2-APB, a TRPM2 channel inhibitor, and prevented by TRPM2-KO. Further analysis indicate that Zn2+ induced ROS production, PARP-1 stimulation, increase in the [Ca2+]c and cell death, all of which were suppressed by chelerythrine, a protein kinase C inhibitor, DPI, a NADPH-dependent oxidase (NOX) inhibitor, GKT137831, a NOX1/4 inhibitor, and Phox-I2, a NOX2 inhibitor. Furthermore, Zn2+-induced PARP-1 stimulation, increase in the [Ca2+]c and cell death were inhibited by PF431396, a Ca2+-sensitive PYK2 inhibitor, and U0126, a MEK/ERK inhibitor. Taken together, our study shows PKC/NOX-mediated ROS generation and PARP-1 activation as an important mechanism in Zn2+-induced TRPM2 channel activation and, TRPM2-mediated increase in the [Ca2+]c to trigger the PYK2/MEK/ERK signalling pathway as a positive feedback mechanism that amplifies the TRPM2 channel activation. Activation of these TRPM2-depenent signalling mechanisms ultimately drives Zn2+-induced Ca2+ overloading and cell death. |
| Databáze: | OpenAIRE |
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