Reactive Oxygen Species Are Required for 5-HT-Induced Transactivation of Neuronal Platelet-Derived Growth Factor and TrkB Receptors, but Not for ERK1/2 Activation
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High concentrations of reactive oxygen species (ROS) induce cellular damage, however at lower concentrations ROS act as intracellular second messengers. In this study, we demonstrate that serotonin (5-HT) transactivates the platelet-derived growth factor (PDGF) type β receptor as well as the TrkB receptor in neuronal cultures and SH-SY5Y cells, and that the transactivation of both receptors is ROS-dependent. Exogenous application of H₂O₂ induced the phosphorylation of these receptors in a dose-dependent fashion, similar to that observed with 5-HT. However the same concentrations of H₂O₂ failed to increase ERK1/2 phosphorylation. Yet, the NADPH oxidase inhibitors diphenyleneiodonium chloride and apocynin blocked both 5-HT-induced PDGFβ receptor phosphorylation and ERK1/2 phosphorylation. The increases in PDGFβ receptor and ERK1/2 phosphorylation were also dependent on protein kinase C activity, likely acting upstream of NADPH oxidase. Additionally, although the ROS scavenger N-acetyl-l-cysteine abrogated 5-HT-induced PDGFβ and TrkB receptor transactivation, it was unable to prevent 5-HT-induced ERK1/2 phosphorylation. Thus, the divergence point for 5-HT-induced receptor tyrosine kinase (RTK) transactivation and ERK1/2 phosphorylation occurs at the level of NADPH oxidase in this system. The ability of 5-HT to induce the production of ROS resulting in transactivation of both PDGFβ and TrkB receptors may suggest that instead of a single GPCR to single RTK pathway, a less selective, more global RTK response to GPCR activation is occurring.
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ROS oxidize -SH groups of cysteine residues in protein kinases A, C, and D, receptor tyrosine kinase, and Ca/calmodulin independent protein kinase II, which phosphorylate target proteins.
“ROS oxidize -SH groups of cysteine residues in protein kinases A, C, and D, receptor tyrosine kinase (RTK), and Ca/calmodulin independent protein kinase II, which in turn phosphorylate target proteins participating in various signaling mechanisms (Kruk et al. 2013).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Kruk et al. 2013
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Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
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Ros and ros-mediated cellular signaling
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- Authors
- Kruk, J. S., Vasefi, M. S., Heikkila, J. J., & Beazely, M. A.
- Affiliations
- University of Waterloo (CA)
- Corresponding author
- Beazely, Michael A.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-09-27
- Volume
- 8
- Issue
- 9
- Pages
- e77027
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3785432
- OpenAlex
- W2011421397
- Cited by
- 31
- References
- 61
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2021: 4 · 2020: 6 · 2019: 1 · 2018: 6 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 4
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Waterloo
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- reactive oxygen species, serotonin, PDGF receptor beta, TrkB receptor, ERK1/2 phosphorylation, receptor tyrosine kinase transactivation, NADPH oxidase, hydrogen peroxide, protein kinase C, SH-SY5Y cells, G protein-coupled receptor signaling
- MeSH terms
- Animals, Enzyme Activation, Humans, Neurons, Phosphorylation, Serotonin, Transcriptional Activation, Reactive Oxygen Species, NADPH Oxidases, Mitogen-Activated Protein Kinase 1, Receptor, Platelet-Derived Growth Factor beta, Receptor, trkB, Cell Line, Tumor, Mitogen-Activated Protein Kinase 3, Mice
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