Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons |
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| Authors: | Kumiko Masuda Hiroyasu Tsutsuki Shingo Kasamatsu Tomoaki Ida Tsuyoshi Takata Kikuya Sugiura Motohiro Nishida Yasuo Watanabe Tomohiro Sawa Takaaki Akaike Hideshi Ihara |
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| Institution: | 1. Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Osaka, Japan;2. Project Management Department, SHIONOGI & CO., LTD., Osaka, Japan;3. Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;4. Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan;5. Department of Pharmacology, Showa Pharmaceutical University, Machida, Tokyo, Japan;6. Department of Veterinary Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan;7. Division of Cardiocirculatory Signaling, National Institute for Physiological Sciences (Okazaki Institute for Integrative Bioscience), National Institutes of Natural Sciences, Aichi, Japan |
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| Abstract: | 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. |
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| Keywords: | nNOS NO/ROS redox signaling 8-nitro-cGMP H-Ras/ERK signaling Neurotoxicity 1-methyl-4-phenylpyridinium NPC12?cells nNOS-expressing PC12?cells CGNs cerebellar granule neurons 8-nitro-cGMP 8-nitroguanosine 3′ 5′-cyclic monophosphate GST DHE dihydroethidium |
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