Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 495, Issue 3, Pages 2165-2170Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2017.12.088
Keywords
nNOS; NO/ROS redox signaling; 8-nitro-cGMP; H-Ras/ERK signaling; MPP+; Neurotoxicity
Categories
Funding
- Ministry of Education, Sciences, Sports, and Technology (MEXT), Japan [S131101]
- Showa Pharmaceutical University for Young Scientists [H28-2]
- [16H04674]
- [15H03115]
- [25253020]
- [26111001]
- Grants-in-Aid for Scientific Research [16H04674, 16K15208, 17K08619, 17K17583, 15K20876, 16K13089, 16H05044, 17K19205, 26111008, 15K20855, 15H03115] Funding Source: KAKEN
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To investigate the role of nitric oxide (NO)/reactive oxygen species (ROS) redox signaling in Parkinson's disease-like neurotoxicity, we used 1-methyl-4-phenylpyridinium (MPP+) treatment (a model of Parkinson's disease). We show that MPP+-induced neurotoxicity was dependent on ROS from neuronal NO synthase (nNOS) in nNOS-expressing PC12 cells (NPC12 cells) and rat cerebellar granule neurons (CGNs). Following MPP+ treatment, we found production of 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), a second messenger in the NO/ROS redox signaling pathway, in NPC12 cells and rat CGNs, that subsequently induced S-guanylation and activation of H-Ras. Additionally, following MPP+ treatment, extracellular signal-related kinase (ERK) phosphorylation was enhanced. Treatment with a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor attenuated MPP+-induced ERK phosphorylation and neurotoxicity. In conclusion, we demonstrate for the first time that NO/ROS redox signaling via 8-nitro-cGMP is involved in MPP+-induced neurotoxicity and that 8-nitro-cGMP activates H-Ras/ERK signaling. Our results indicate a novel mechanism underlying MPP+-induced neurotoxicity, and therefore contribute novel insights to the mechanisms underlying Parkinson's disease. (C) 2017 Elsevier Inc. All rights reserved.
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