The mouse Slc39a8 gene encodes the ZIPS transporter, which has been shown to be a divalent cation/HCO3- symporter. Using ZIPS cRNA-injected Xenopus oocyte cultures, we show herein that: [a] ZIP8-mediated cadmium (Cd2+) and zinc (Zn2+) uptake have V-max values of 1.8 +/- 0.08 and 1.0 +/- 0.08 pmol/oocyte/h, and K-m values of 0.48 +/- 0.08 and 0.26 +/-0.09 mu M, respectively; [b] ZIP8-mediated Cd2+ uptake is most inhibited by Zn2+ second-best inhibited by Cu2+, Pb2+ and Hg2+, and not inhibited by Mn2+ or Fe2+; and [c] electrogenicity studies demonstrate an influx of two HCO3- anions per one Cd2+ (or one Zn2+) cation, i.e. electroneutral complexes. Using Madin-Darby canine kidney (MDCK) polarized epithelial cells retrovirally infected with ZIPS cDNA and tagged with hemagglutinin at the C-terminus. we show that-similar to ZIP4-the ZIP8 eight-transmembrane protein is largely internalized during Zn2+ homeostasis, but moves predominantly to the cell surface membrane (trafficking) under conditions of Zn2+ depletion. (C) 2007 Elsevier Inc. All rights reserved.