Inhibition of PTEN by peroxynitrite activates the phosphoinositide‐3‐kinase/Akt neuroprotective signaling pathway
Open accessAbstract
Peroxynitrite is usually considered as a neurotoxic nitric oxide‐derivative. However, an increasing body of evidence suggests that, at low concentrations, peroxynitrite affords transient cytoprotection, both in vitro and in vivo. Here, we addressed the signaling mechanism responsible for this effect, and found that rat cortical neurons in primary culture acutely exposed to peroxynitrite (0.1 mmol/L) rapidly elicited Akt‐Ser 473 phosphorylation. Inhibition of phosphoinositide‐3‐kinase (PI3K)/Akt pathway with wortmannin or Akt small hairpin RNA (shRNA) abolished the ability of peroxynitrite to prevent etoposide‐induced apoptotic death. Endogenous peroxynitrite formation by short‐term incubation of neurons with glutamate stimulated Akt‐Ser 473 phosphorylation, whereas Akt shRNA enhanced the vulnerability of neurons against glutamate. We further show that Akt‐Ser 473 phosphorylation was consequence of the oxidizing, but not the nitrating properties of peroxynitrite. Peroxynitrite failed to nitrate or phosphorylate neurotrophin tyrosine kinase receptors (Trks), and it did not modify the ability of brain‐derived neurotrophic factor (BDNF), to phosphorylate its cognate receptor, TrkB; however, peroxynitrite enhanced BDNF‐mediated Akt‐Ser 473 phosphorylation. Finally, we found that peroxynitrite‐stimulated Akt‐Ser 473 phosphorylation was associated with an increased proportion of oxidized phosphoinositide phosphatase, PTEN, in neurons. Moreover, peroxynitrite prevented the increase of apoptotic neuronal death caused by over‐expression of PTEN. Thus, peroxynitrite exerts neuroprotection by inhibiting PTEN, hence activating the anti‐apoptotic PI3K/Akt pathway in primary neurons.
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- Authors
- Delgado‐Esteban, M., Martin‐Zanca, D., Andres‐Martin, L., Almeida, A., & Bolaños, J. P.
- Affiliations
- Universidad de Salamanca (ES)
- Corresponding author
- Bolaños, Juan P.
- ORCID
- Bolaños, Juan P.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2007-01-22
- Volume
- 102
- Issue
- 1
- Pages
- 194-205
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1981755281
- Cited by
- 78
- References
- 54
- Citations by year
- 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 8 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 5 · 2015: 6 · 2014: 2 · 2013: 3 · 2012: 5
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Gredos (University of Salamanca) (submittedVersion, cc-by-nc-nd)
- Hispana (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- peroxynitrite, PTEN, phosphoinositide 3-kinase/Akt pathway, neuroprotection, Akt Ser473 phosphorylation, glutamate excitotoxicity, etoposide-induced apoptosis, BDNF/TrkB signaling, oxidative stress
- MeSH terms
- Antineoplastic Agents, Phytogenic, Cells, Cultured, Cerebral Cortex, Etoposide, Flow Cytometry, Humans, NADP, Nerve Degeneration, Oxidation-Reduction, Phosphorylation, Plasmids, RNA, Transfection, Blotting, Western, Signal Transduction, Apoptosis, Neuroprotective Agents, Phosphatidylinositol 3-Kinases, Peroxynitrous Acid, Immunoprecipitation, Oncogene Protein v-akt, PTEN Phosphohydrolase
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