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ZIP8, Member of the Solute-Carrier-39 (SLC39) Metal-Transporter Family: Characterization of Transporter Properties

Department of Environmental Health, and the Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio (L.H., K.G., T.P.D., J.R., D.W.N.); and Department of Internal Medicine, Division of Nephrology and Hypertension, University of Cincinnati Medical Center, Cincinnati, Ohio (H.L., M.S.)

Cadmium is a dangerous metal distributed widely in the environment. Members of our laboratory recently identified the ZIP8 transporter protein, encoded by the mouse Slc39a8 gene, to be responsible for genetic differences in response to cadmium damage of the testis. Stable retroviral infection of the ZIP8 cDNA in mouse fetal fibroblast cultures (rvZIP8 cells) leads to as much as a 10-fold increase in the rate of intracellular cadmium influx and accumulation. In the present study, we showed that cadmium uptake operated maximally at pH 7.5 and a temperature of 37°C and was inhibited by cyanide. Of more than a dozen cations tested, manganese(II) was the best competitive cation for cadmium uptake. The K_m for Cd²⁺ uptake was 0.62 µM, and the K_m for Mn²⁺ uptake was 2.2 µM; thus, manganese is probably the physiological substrate for ZIP8. Cadmium uptake was independent of sodium, potassium or chloride ions, but strongly dependent on the presence of bicarbonate. By Western blot analysis of rvZIP8 cells, we showed that ZIP8 protein was glycosylated. Using Z-stack confocal microscopy in Madin-Darby canine kidney polarized epithelial cells, we found that ZIP8 was localized on the apical side—implying an important role for manganese or cadmium uptake and disposition. It is likely that ZIP8 is a symporter, that a gradient across the plasma membrane acts as the driving force for manganese uptake, and that cadmium is a rogue hitchhiker displacing manganese to cause cadmium-associated disease.

Address correspondence to: Dr. 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

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