TY - JOUR T1 - <em>Slc39a14</em> Gene Encodes ZIP14, A Metal/Bicarbonate Symporter: Similarities to the ZIP8 Transporter JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1413 LP - 1423 DO - 10.1124/mol.107.043588 VL - 73 IS - 5 AU - Kuppuswami Girijashanker AU - Lei He AU - Manoocher Soleimani AU - Jodie M. Reed AU - Hong Li AU - Zhiwei Liu AU - Bin Wang AU - Timothy P. Dalton AU - Daniel W. Nebert Y1 - 2008/05/01 UR - http://molpharm.aspetjournals.org/content/73/5/1413.abstract N2 - 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. ER -