Abstract
Oxidative stress induced by reactive oxygen species (ROS) is associated with various neurological disorders including aging, neurodegenerative diseases, as well as traumatic and ischemic insults. Astrocytes have an important role in the anti-oxidative defense in the brain. The gap junction protein connexin43 (Cx43) forms intercellular channels as well as hemichannels in astrocytes. In the present study, we investigated the contribution of Cx43 to astrocytic death induced by the ROS hydrogen peroxide (H2O2) and the mechanism by which Cx43 exerts its effects. Lack of Cx43 expression or blockage of Cx43 channels resulted in increased ROS-induced astrocytic death, supporting a cell protective effect of functional Cx43 channels. H2O2 transiently increased hemichannel activity, but reduced gap junction intercellular communication (GJIC). GJIC in wild-type astrocytes recovered after 7 h, but was absent in Cx43 knock-out astrocytes. Blockage of Cx43 hemichannels incompletely inhibited H2O2-induced hemichannel activity, indicating the presence of other hemichannel proteins. Panx1, which is predicted to be a major hemichannel contributor in astrocytes, did not appear to have any cell protective effect from H2O2 insults. Our data suggest that GJIC is important for Cx43-mediated ROS resistance. In contrast to hypoxia/reoxygenation, H2O2 treatment decreased the ratio of the hypophosphorylated isoform to total Cx43 level. Cx43 has been reported to promote astrocytic death induced by hypoxia/reoxygenation. We therefore speculate the increase in Cx43 dephosphorylation may account for the facilitation of astrocytic death. Our findings suggest that the role of Cx43 in response to cellular stress is dependent on the activation of signaling pathways leading to alteration of Cx43 phosphorylation states.
Highlights
The gap junction protein Cx43 is implicated in maintaining anti-oxidative defense in astrocytes
To determine whether functional Cx43 channels are important for protection against H2O2, astrocytes were exposed to the Cx43 channel blockers carbenoxelone (Cbx) or 18-␣-glycyrrhetinic acid (18-␣GA), which have been previously shown to inhibit both astrocytic Cx43 gap junction coupling and hemichannel activity [36]
The role for Cx43 channels in H2O2-induced cell death has been studied in several cell types, including epithelial cells and osteocytes, with mixed results
Summary
The gap junction protein Cx43 is implicated in maintaining anti-oxidative defense in astrocytes. Results: In contrast to hypoxia/reoxygenation, oxidative stress induced by H2O2 triggers more astrocytic death in the absence of Cx43 channels. The gap junction protein connexin (Cx43) forms intercellular channels as well as hemichannels in astrocytes. Lack of Cx43 expression or blockage of Cx43 channels resulted in increased ROS-induced astrocytic death, supporting a cell protective effect of functional Cx43 channels. Astrocytes are the most abundant non-neuronal cell type in the central nervous system [1] They play an essential role in adult brain homeostasis, including glutamate uptake, potassium ion buffering, nutrient support, and antioxidant protection for neurons [2,3,4,5]. The mechanism underlying this Cx43mediated ROS resistance in astrocytes has not been investigated, several lines of evidence indicate the involve-
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