title: 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.
authors.affiliation: From the Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, V6T 1Z3 Canada.
authors.forename: Hoa T
authors.initials: HT
authors.lastname: Le
authors.forename: Wun Chey
authors.initials: WC
authors.lastname: Sin
authors.forename: Shannon
authors.initials: S
authors.lastname: Lozinsky
authors.forename: John
authors.initials: J
authors.lastname: Bechberger
authors.forename: José Luis
authors.initials: JL
authors.lastname: Vega
authors.forename: Xu Qiu
authors.initials: XQ
authors.lastname: Guo
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
authors.forename: Christian C
authors.initials: CC
authors.lastname: Naus
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D018031:Connexin 43; D017630:Connexins; D009419:Nerve Tissue Proteins; D016877:Oxidants; C503631:Panx1 protein, mouse; D006861:Hydrogen Peroxide
keywords: Astrocytes; Connexin; Gap Junctions; Hemichannels; Hydrogen Peroxide; Hypoxia; Hypoxia/Reoxygenation