title: Reduced connexin43 expression correlates with c-Src activation, proliferation, and glucose uptake in reactive astrocytes after an excitotoxic insult.
abstract: In diverse brain pathologies, astrocytes become reactive and undergo profound phenotypic changes. Connexin43 (Cx43), the main gap junction channel-forming protein in astrocytes, is one of the proteins modified in reactive astrocytes. Downregulation of Cx43 in cultured astrocytes activates c-Src, promotes proliferation, and increases the rate of glucose uptake; however, so far there have been no studies examining whether this cascade of events takes place in reactive astrocytes. In this work, we analyzed this pathway after a cortical lesion induced by a kainic acid injection. As previously described, astrocytes reacted to the lesion with an increase in glial fibrillary acidic protein and a decrease in Cx43 expression. Some of these reactive astrocytes proliferated, as estimated by bromodeoxyuridine incorporation and cyclins D1 and D3 upregulation. In addition, the expression of the glucose transporter GLUT-3 and the enzyme responsible for glucose phosphorylation, Type II hexokinase (Hx-2), were induced in reactive astrocytes, suggesting an increased glucose uptake. Previous in vitro studies reported that c-Src is the link between Cx43 and glucose uptake and proliferation in astrocytes. Here, we found that c-Src activity increased in the lesioned area. c-Src activation and Cx43 downregulation preceded the peak of Hx-2 and cyclin D3 expression, suggesting that c-Src could mediate the effect of Cx43 on glucose uptake and proliferation in reactive astrocytes after an excitotoxic insult. Interestingly, we identify c-Src, GLUT-3, and Hx-2 in the signaling mechanisms involved in the reaction of astroglia to injury. Altogether these data contribute to identify new therapeutical targets to enhance astrocyte neuroprotective activities.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Gangoso
authors.forename: Pascal
authors.initials: P
authors.lastname: Ezan
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Valle-Casuso
authors.forename: Sandra
authors.initials: S
authors.lastname: Herrero-González
authors.forename: Annette
authors.initials: A
authors.lastname: Koulakoff
authors.forename: Jose M
authors.initials: JM
authors.lastname: Medina
authors.forename: Christian
authors.initials: C
authors.lastname: Giaume
authors.forename: Arantxa
authors.initials: A
authors.lastname: Tabernero
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D018031:Connexin 43 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D016391:Genes, src / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D018031:Connexin 43; D018690:Excitatory Amino Acid Agonists; D005947:Glucose; D007608:Kainic Acid