Protein kinase B (AKT) upregulation and Thy-1-α<sub>v</sub>β<sub>3</sub> integrin-induced phosphorylation of Connexin43 by activated AKT in astrogliosis.

Détails

Ressource 1Télécharger: 224. Pérez-Núñez et al.pdf (4854.91 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_9764A8B87F3E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Protein kinase B (AKT) upregulation and Thy-1-α<sub>v</sub>β<sub>3</sub> integrin-induced phosphorylation of Connexin43 by activated AKT in astrogliosis.
Périodique
Journal of neuroinflammation
Auteur⸱e⸱s
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 AFG, Leyton L.
ISSN
1742-2094 (Electronic)
ISSN-L
1742-2094
Statut éditorial
Publié
Date de publication
06/01/2023
Peer-reviewed
Oui
Volume
20
Numéro
1
Pages
5
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
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 <sub>v</sub> β <sub>3</sub> 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.
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 <sup>G93A</sup> 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).
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 <sup>G93A</sup> 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.
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.
Mots-clé
Animals, Mice, Rats, Adenosine Triphosphate/pharmacology, Adenosine Triphosphate/metabolism, Astrocytes/metabolism, Brain Injuries/metabolism, Connexin 43/metabolism, Gliosis/metabolism, Inflammation/metabolism, Integrin beta3/genetics, Integrin beta3/metabolism, Integrin beta3/pharmacology, Phosphatidylinositol 3-Kinases/metabolism, Phosphorylation, Proto-Oncogene Proteins c-akt/metabolism, Up-Regulation, Thy-1 Antigens/metabolism, Integrin alpha5/metabolism, ALS model, Astrogliosis, Bioinformatics analysis, Brain damage, Connexin43, Inflammation, PI3K/AKT signaling pathway
Pubmed
Web of science
Open Access
Oui
Création de la notice
17/01/2023 9:18
Dernière modification de la notice
07/02/2023 6:56
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