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.

Connexin-based channels contribute to metabolic pathways in the oligodendroglial lineage

“…Finally, we used a conditional astrocytic Cx43 knockout (Cx43-KO) mouse as a glucose-deprivation model to confirm the importance of connexin-channel-based energy support on the OPC proliferation in both in vivo and co-culture systems. In these mice, glucose uptake in Cx43 lacking astrocytes is increased by compensatory upregulation of Glut1, Glut3 and type I/II hexokinase expression (Gangoso et al, 2012;Tabernero et al, 2006). As predicted, we observed that OPC proliferation was inhibited by Cx43 deletion in astrocytes without impacting on OPC hemichannel properties.…”

“…It has been reported that in astrocytes, Cx43 deletion increases glucose uptake by a compensatory upregulation of Glut transporters and/or glucose metabolism enzymes (Gangoso et al, 2012). To determine the influence of astroglial glucose over-consumption on the oligodendroglial lineage, we used the astrocyte Cx43 conditional knockout mouse (hGFAP Cre/+ :Cx43 fl/fl , Cx43-KO).…”

Tumor necrosis factor-mediated downregulation of spinal astrocytic connexin43 leads to increased glutamatergic neurotransmission and neuropathic pain in mice

“…Cx43 is co-localized with b-catenin in cell membranes, sequestering this protein and negatively modulating b-catenin-dependent gene transcription in cardiac myocytes (Ai et al, 2000). Downregulation of Cx43 increases the expression of glucose transporter GLUT-3 through the activation of c-Src in cultured astrocytes (Gangoso et al, 2012). Cx43 has also been shown to modulate the expression of a number of genes (Iacobas et al, 2004).…”

Triggering of Protection Mechanism against Phoneutria nigriventer Spider Venom in the Brain

“…PNV contains excitotoxic neuropeptides [11] and PnTx1-3, a neurotoxin isolated from PNV, has been shown to increase the frequency of Ca 2+ oscillations in in vitro GH3 cells [44]. The significant further reduction of Cx43 expression, especially in the hippocampus (5 h post-PNV), could be a mechanism for avoiding cell damage [45], since PNV induces FOS induction (2 h post-PNV) in neurons [6] and the decrease of gap junctions (GJs) formation/communication in astrocytes could be controlled by neurons [42].…”