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⁺ (K_m = 0.14 versus 1.1 μM) and Mn²⁺ uptake (K_m = 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.