title: Connexin43 hemichannels contribute to cadmium-induced oxidative stress and cell injury.
abstract: We investigated the potential involvement of connexin hemichannels in cadmium ions (Cd(2+))-elicited cell injury. Transfection of LLC-PK1 cells with a wild-type connexin43 (Cx43) sensitized them to Cd(2+)-elicited cell injury. The cell susceptibility to Cd(2+) was increased by depletion of glutathione (GSH) with DL-buthionine-[S,R]-sulfoximine, and decreased by N-acetyl-cysteine or glutathione reduced ethyl ester. Fibroblasts derived from Cx43 wild-type (Cx43+/+) and knockout (Cx43-/-) fetal littermates displayed different susceptibility to Cd(2+). Cd(2+) induced a higher concentration of reactive oxygen species, a stronger activation c-Jun N-terminal kinase, and significantly more severe cell injury in Cx43+/+ fibroblasts, as compared with Cx43-/- fibroblasts. Cd(2+) caused a reduction in intracellular GSH, whereas it elevated extracellular GSH. This effect of Cd(2+) was more dramatic in Cx43+/+ than Cx43-/- fibroblasts. Treatment of Cx43+/+ fibroblasts with Cd(2+) caused a Cx43 hemichannel-dependent influx of Lucifer Yellow and efflux of ATP. Collectively, our study demonstrates that Cx43 sensitizes cells to Cd(2+)-initiated cytotoxicity, possibly through hemichannel-mediated effects on intracellular oxidative status.
authors.affiliation: Department of Molecular Signaling, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Fang
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Qiaojing
authors.initials: Q
authors.lastname: Yan
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chi
authors.forename: Jean X
authors.initials: JX
authors.lastname: Jiang
authors.forename: Peiyu
authors.initials: P
authors.lastname: Wang
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsue
authors.forename: Masanori
authors.initials: M
authors.lastname: Kitamura
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013552:Swine
chemical_list: D018031:Connexin 43; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D002104:Cadmium; D005978:Glutathione; D000111:Acetylcysteine