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

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dc.article.number5
dc.catalogadorpva
dc.contributor.authorPérez-Núñez, Ramón
dc.contributor.authorChamorro, Alejandro
dc.contributor.authorGonzález, María F.
dc.contributor.authorContreras, Pamela
dc.contributor.authorArtigas Barrenechea, Rocío
dc.contributor.authorCorvalán R., Alejandro
dc.contributor.authorvan Zundert, Brigitte
dc.contributor.authorReyes, Christopher
dc.contributor.authorMoya, Pablo R.
dc.contributor.authorAvalos, Ana M.
dc.contributor.authorSchneider, Pascal
dc.contributor.authorQuest, Andrew F. G.
dc.contributor.authorLeyton, Lisette
dc.date.accessioned2023-03-07T13:17:38Z
dc.date.available2023-03-07T13:17:38Z
dc.date.issued2023
dc.date.updated2023-01-08T01:05:10Z
dc.description.abstractBackground: 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 αvβ3 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 hSOD1G93A 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 hSOD1G93A 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.
dc.fechaingreso.objetodigital2023-01-08
dc.format.extent19 páginas
dc.fuente.origenAutoarchivo
dc.identifier.citationJournal of Neuroinflammation. 2023 Jan 06;20(1):5
dc.identifier.doi10.1186/s12974-022-02677-7
dc.identifier.urihttps://doi.org/10.1186/s12974-022-02677-7
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/66534
dc.information.autorucFacultad de ciencias biológicas ; Artigas Barrenechea, Rocío ; S/I ; 9174
dc.information.autorucFacultad de medicina ; Corvalán R., Alejandro ; 0000-0001-5492-3853 ; 63885
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final19
dc.pagina.inicio1
dc.revistaJournal of Neuroinflammation
dc.rightsacceso abierto
dc.rights.holderThe Author(s)
dc.subjectBrain damagees_ES
dc.subjectInflammationes_ES
dc.subjectAstrogliosises_ES
dc.subjectALS modeles_ES
dc.subjectBioinformatics analysises_ES
dc.subjectPI3K/AKT signaling pathwayes_ES
dc.subjectConnexin43es_ES
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.titleProtein kinase B (AKT) upregulation and Thy‑1‑αvβ3 integrin‑induced phosphorylation of Connexin43 by activated AKT in astrogliosises_ES
dc.typeartículo
dc.volumen20
sipa.codpersvinculados9174
sipa.codpersvinculados63885
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