Gap Junction Intercellular Communication Mediated by Connexin43 in Astrocytes Is Essential for Their Resistance to Oxidative Stress

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.

Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury

“…28 Hypoxia/ischemia induces dephosphorylation of these sites thereby leading to a reduced activity of gap junction, relocation of Cx43 proteins and enhanced degradation. 29 Cx43 mutants with these sites replaced by phosphomimetic glutamic acids (Cx43-S3E) are resistant to pathological gap junction remodeling induced by cardiac ischemia. 19 As shown in Figure 3E, hypoxia reduced ACM redifferentiation and infection of NRVM with Cx43-S3E rescued the inhibitory effect of hypoxia on ACM redifferentiation.…”

Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals

“…To address this with a pharmacological rather than a genetic approach, we utilized the Cx43 channel blocker 18-α-glycyrrhetinic acid (AGA) and our previously published “brain beiging” model, which activates sympathetic signals by doxycycline-induced expression of Xbp1s protein in POMC neurons (Williams et al, 2014) to investigate the role of Cx43 in sympathetic innervation regulated WAT beiging. AGA has been used to uncouple gap junction channels in various cell culture models, via suggested mechanisms involving phosphorylation or changes in the aggregation of connexin subunits (Dhein, 2004; Le et al, 2014). Administration of AGA in the diet significantly reduces LY coupling in beige adipocytes (Suppl.…”

Astrocytes promote glioma invasion via the gap junction protein connexin43

“…If astrogliosis induced by different brain insults share the same basic mechanisms, it is then not surprising that hemichannels may be preferentially closed in tumorigenesis, as opening of Cx43 hemichannels appears to peak at 3 days post infection. 71 Therefore, the transient opening of Cx43 hemichannels in response to cellular stress 101,102 indicates their roles will probably be restricted to acute events. In contrast, robust intercellular dye transfer, indicating strong GJIC, was observed in the gliosis region.…”