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Cited by 24Connexins and lens biologyNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular Disturbances

Protein kinase B (AKT) upregulation and Thy-1-αvβ3 integrin-induced phosphorylation of Connexin43 by activated AKT in astrogliosis

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Pérez-Núñez, Ramón, Chamorro, Alejandro, González, María Fernanda, Contreras, Pamela, Artigas, Rocío, Corvalán, Alejandro H., van Zundert, Brigitte, Reyes, Christopher +5 more·2023·Journal of Neuroinflammation
DOI 10.1186/s12974-022-02677-7PMC PMC9817390
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Abstract

Background: In response to brain injury or inflammation, astrocytes undergo hypertrophy, proliferate, and migrate to the damaged zone. These changes, collectively known as "astrogliosis", initially protect the brain; however, astrogliosis can also cause neuronal dysfunction. Additionally, these astrocytes undergo intracellular changes involving alterations in the expression and localization of many proteins, including α v β 3 integrin. Our previous reports indicate that Thy-1, a neuronal glycoprotein, binds to this integrin inducing Connexin43 (Cx43) hemichannel (HC) opening, ATP release, and astrocyte migration. Despite such insight, important links and molecular events leading to astrogliosis remain to be defined. Methods: Using bioinformatics approaches, we analyzed different Gene Expression Omnibus datasets to identify changes occurring in reactive astrocytes as compared to astrocytes from the normal mouse brain. In silico analysis was validated by both qRT-PCR and immunoblotting using reactive astrocyte cultures from the normal rat brain treated with TNF and from the brain of a hSOD1 G93A transgenic mouse model. We evaluated the phosphorylation of Cx43 serine residue 373 (S373) by AKT and ATP release as a functional assay for HC opening. In vivo experiments were also performed with an AKT inhibitor (AKTi). Results: The bioinformatics analysis revealed that genes of the PI3K/AKT signaling pathway were among the most significantly altered in reactive astrocytes. mRNA and protein levels of PI3K, AKT, as well as Cx43, were elevated in reactive astrocytes from normal rats and from hSOD1 G93A transgenic mice, as compared to controls. In vitro, reactive astrocytes stimulated with Thy-1 responded by activating AKT, which phosphorylated S373Cx43. Increased pS373Cx43 augmented the release of ATP to the extracellular medium and AKTi inhibited these Thy-1-induced responses. Furthermore, in an in vivo model of inflammation (brain damage), AKTi decreased the levels of astrocyte reactivity markers and S373Cx43 phosphorylation. Conclusions: Here, we identify changes in the PI3K/AKT molecular signaling network and show how they participate in astrogliosis by regulating the HC protein Cx43. Moreover, because HC opening and ATP release are important in astrocyte reactivity, the phosphorylation of Cx43 by AKT and the associated increase in ATP release identify a potential therapeutic window of opportunity to limit the adverse effects of astrogliosis.

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  • PI3K-Akt signaling can regulate actin activity and is important in astrocyte proliferation and migration.

    “It has been suggested that PI3K-Akt signaling can regulate actin activity and is important in astrocyte proliferation and migration (Zhao et al., 2017;Liao et al., 2022;Pérez-Núñez et al., 2023).”

    From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Pérez-Núñez et al., 2023

    The Discussion (page unavailable) says PI3K/AKT signaling regulates reactive astrocyte proliferation and participates in migration. The Background and Discussion identify regulation of the actin cytoskeleton as another altered pathway, but do not establish that PI3K/AKT signaling regulates actin activity. (LLM, conf=0.85)

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Authors
Pérez-Núñez, R., Chamorro, A., González, M. F., Contreras, P., Artigas, R., Corvalán, A. H., van Zundert, B., Reyes, C., Moya, P. R., Avalos, A. M., Schneider, P., Quest, A. F. G., & Leyton, L.
Affiliations
  • Advanced Center for Chronic Diseases (CL)
  • Pontificia Universidad Católica de Chile (CL)
  • University of Valparaíso (CL)
  • Universidad Autónoma de Chile (CL)
  • University of Lausanne (CH)
Corresponding author
Leyton, Lisette
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2023-01-06
Volume
20
Issue
1
Pages
5-5
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-022-02677-7
PMC
PMC9817390
OpenAlex
W4313575466
Cited by
24
References
5
Citations by year
2026: 5 · 2025: 6 · 2024: 9 · 2023: 4
FWCI
2.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IRIS (submittedVersion, cc-by)
  • Repositorio Institucional Académico , Sistema de Bibliotecas Universidad Andrés Bello (UNAB) (Universidad Andrés Bello (UNAB)) (submittedVersion, cc-by)
Funders
  • Agencia Nacional de Investigación y Desarrollo (FONDECYT #3170645 (RP), FONDECYT #1191928 (AHC), Anillo ACT-1114, and DRI USA 2013-0030 (BvZ), FONDECYT #1190833 (PRM), CONICYT-FONDAP #15130011 (AFGQ and AHC), FONDECYT #1200836 (LL))
  • ALS Therapy Alliance (ATA 2014-F-034)
  • Universidad Autónoma de Chile, Chile (DIUA 169-2019)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003-176256)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
astrocyte activation, Akt, PI3K/Akt signaling, connexin 43, CD90, integrin αvβ3, ATP release, reactive astrocytes, neuroinflammation, AKT inhibitors, astrocyte migration
MeSH terms
Adenosine Triphosphate, Animals, Astrocytes, Brain Injuries, Gliosis, Inflammation, Phosphorylation, Up-Regulation, Connexin 43, Thy-1 Antigens, Phosphatidylinositol 3-Kinases, Integrin alpha5, Integrin beta3, Proto-Oncogene Proteins c-akt, Mice, Rats

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