title: Zinc- and bicarbonate-dependent ZIP8 transporter mediates selenite uptake.
abstract: Selenite (HSeO3-) is a monovalent anion of the essential trace element and micronutrient selenium (Se). In therapeutic concentrations, HSeO3- has been studied for treating certain cancers, serious inflammatory disorders, and septic shock. Little is known, however, about HSeO3- uptake into mammalian cells; until now, no mammalian HSeO3- uptake transporter has been identified. The ubiquitous mammalian ZIP8 divalent cation transporter (encoded by the SLC39A8 gene) is bicarbonate-dependent, moving endogenous substrates (Zn2+, Mn2+, Fe2+ or Co2+) and nonessential metals such as Cd2+ into the cell. Herein we studied HSeO3- uptake in: human and mouse cell cultures, shRNA-knockdown experiments, Xenopus oocytes, wild-type mice and two transgenic mouse lines having genetically altered ZIP8 expression, and mouse erythrocytes ex vivo. In mammalian cell culture, excess Zn2+ levels and/or ZIP8 over-expression can be associated with diminished viability in selenite-treated cells. Intraperitoneal HSeO3- causes the largest ZIP8-dependent increases in intracellular Se content in liver, followed by kidney, heart, lung and spleen. In every model system studied, HSeO3- uptake is tightly associated with ZIP8 protein levels and sufficient Zn2+ and HCO3- concentrations, suggesting that the ZIP8-mediated electroneutral complex transported contains three ions: Zn2+/(HCO3-)(HSeO3-). Transporters having three different ions in their transport complex are not without precedent. Although there might be other HSeO3- influx transporters as yet undiscovered, data herein suggest that mammalian ZIP8 plays a major role in HSeO3- uptake.
authors.affiliation: Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: McDermott
authors.affiliation: Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Geng
authors.affiliation: Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Gálvez-Peralta
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.affiliation: Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA.
authors.forename: Zijuan
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000502:physiology*; D051379:Mice; D020887:Selenious Acid / Q000378:metabolism*; D014981:Xenopus; D015032:Zinc / Q000378:metabolism
chemical_list: D001639:Bicarbonates; D027682:Cation Transport Proteins; D020887:Selenious Acid; D015032:Zinc
keywords: ZIP8; membrane-bound transporter; micronutrient; selenite; zinc