Slc39a14 Gene Encodes ZIP14, A Metal/Bicarbonate Symporter: Similarities to the ZIP8 Transporter
- Kuppuswami Girijashanker,
- Lei He,
- Manoocher Soleimani,
- Jodie M. Reed,
- Hong Li,
- Zhiwei Liu,
- Bin Wang,
- Timothy P. Dalton and
- Daniel W. Nebert
- Department of Environmental Health and Center for Environmental Genetics (K.G., L.H., J.M.R., Z.L., B.W., T.P.D., D.W.N.) and Department of Internal Medicine, Division of Nephrology and Hypertension (H.L., M.S.), University of Cincinnati Medical Center, Cincinnati, Ohio
- Address correspondence to:
Daniel W. Nebert, Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056. E-mail dan.nebert{at}uc.edu
Abstract
The mouse and human genomes contain 14 highly conserved SLC39 genes. Viewed from an evolutionary perspective, SLC39A14 and SLC39A8 are the most closely related, each having three noncoding exons 1. However, SLC39A14 has two exons 4, giving rise to Zrt- and Irt-related protein (ZIP)ZIP14A and ZIP14B alternatively spliced products. C57BL/6J
mouse ZIP14A expression is highest in liver, duodenum, kidney, and testis; ZIP14B expression is highest in liver, duodenum,
brain, and testis; and ZIP8 is highest in lung, testis, and kidney. We studied ZIP14 stably retroviral-infected mouse fetal
fibroblast cultures and transiently transfected Madin-Darby canine kidney (MDCK) polarized epithelial cells. Our findings
include: 1) ZIP14-mediated cadmium uptake is proportional to cell toxicity, but manganese is not; 2) ZIP14B has a higher affinity
than ZIP14A toward Cd2+ (Km = 0.14 versus 1.1 μM) and Mn2+ uptake (Km = 4.4 versus 18.2 μM); 3) ZIP14A- and ZIP14B-mediated Cd2+ uptake is most inhibited by Zn2+, and next by Mn2+ and Cu2+; 4) like ZIP8, ZIP14A- and ZIP14B-mediated Cd2+ uptake is dependent on extracellular 
; 5) like ZIP8, ZIP14 transporters are localized on the apical surface of MDCK-ZIP cells; and 6) like ZIP8, ZIP14 proteins
are glycosylated. Tissues such as intestine and liver, located between the environment and the animal, show high levels of
ZIP14; given the high affinity for ZIP14, Cd2+ is likely to act as a rogue hitchhiker—displacing Zn2+ or Mn2+ and entering the body to cause unwanted cell damage and disease.
Footnotes
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This work was supported in part by National Institutes of Health grants R01-ES10416 (to D.W.N.), R01-DK62809 (to M.S), and P30-ES06096 (to T.P.D., D.W.N.)
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K.G. and L.H. contributed equally to this work and are co-first authors.
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This work has been presented in part at the 45th Annual Meeting of the Society of Toxicology; 2006 Mar 5-9; San Diego, CA, and the 46th Annual Meeting of the Society of Toxicology; 2007 Mar 25-29; Charlotte, NC.
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ABBREVIATIONS: ZIP, Zrt- and Irt-related protein; TM, transmembrane domain; HBSS, Hanks' balanced salt solution; MFF, mouse fetal fibroblast; MDCK, Madin-Darby canine kidney; PCR, polymerase chain reaction; bp, base pair(s); HA, hemagglutinin; DIDS, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid; PNGase F, peptide N-glycosidase F [peptide-N4-(N-acetyl-β-glucosaminyl)asparagine amidase]; SLC, solute carrier; dbEST, database for expressed sequence tags; rvZIP14, vZIP8, rvZIP4, rvLUC, retrovirally infected MFF cells expressing ZIP or firefly luciferase; NBC1, sodium-bicarbonate-1 cotransporter; vMDCK-ZIP14, MDCK-ZIP8, transiently transfected MDCK cells expressing ZIP or firefly luciferase; PBS, phosphate-buffered saline.
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- Received November 18, 2007.
- Accepted February 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
