| First Author | Miyake T | Year | 2014 |
| Journal | Biochem Biophys Res Commun | Volume | 444 |
| Issue | 2 | Pages | 212-7 |
| PubMed ID | 24462864 | Mgi Jnum | J:218140 |
| Mgi Id | MGI:5616712 | Doi | 10.1016/j.bbrc.2014.01.022 |
| Citation | Miyake T, et al. (2014) TRPM2 contributes to LPS/IFNgamma-induced production of nitric oxide via the p38/JNK pathway in microglia. Biochem Biophys Res Commun 444(2):212-7 |
| abstractText | Microglia are immune cells that maintain brain homeostasis at a resting state by surveying the environment and engulfing debris. However, in some pathological conditions, microglia can produce neurotoxic factors such as pro-inflammatory cytokines and nitric oxide (NO) that lead to neuronal degeneration. Inflammation-induced calcium (Ca(2+)) signaling is thought to underlie this abnormal activation of microglia, but the mechanisms are still obscure. We previously showed that combined application of lipopolysaccharide and interferon gamma (LPS/IFNgamma) induced-production of NO in microglia from wild-type (WT) mice is significantly reduced in microglia from transient receptor potential melastatin 2 (TRPM2)-knockout (KO) mice. Here, we found that LPS/IFNgamma produced a late-onset Ca(2+) signaling in WT microglia, which was abolished by application of the NADPH oxidase inhibitor diphenylene iodonium (DPI) and ML-171. In addition, pharmacological blockade or gene deletion of TRPM2 channel in microglia did not show this Ca(2+) signaling. Furthermore, pharmacological manipulation and Western blotting revealed that Ca(2+) mobilization, the proline-rich tyrosine kinase 2 (Pyk2), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) contributed to TRPM2-mediated LPS/IFNgamma-induced activation, while the extracellular signal-regulated protein kinase (ERK) did not. These results suggest that LPS/IFNgamma activates TRPM2-mediated Ca(2+) signaling, which in turn increases downstream p38 MAPK and JNK signaling and results in increased NO production in microglia. |
