Slc39a14 Gene Encodes ZIP14, A Metal/Bicarbonate Symporter: Similarities to the ZIP8 Transporter

Cadmium is a toxic nonessential divalent cation classified by International Agency for Research on Cancer (Lyon, France) as a “Category I” human lung carcinogen. Acute doses lead to immediate damage in the central nervous system, lung, bone, gastrointestinal tract, liver, placenta, developing embryo, ovary, and testis (Waisberg et al., 2003; Zalups and Ahmad, 2003). Long-term exposure to low Cd2+ doses primarily causes renal proximal tubular metabolic acidosis and osteomalacia (renal Fanconi syndrome); Cd2+ is eliminated very slowly from the body and thus accumulates (predominantly in kidney, less in liver) as a total body burden with age. Sources of Cd2+ include cigarette smoke, contaminated soil (around metal-smelting operations), and polluted foods such as shellfish. Curiously, tobacco plants take up and concentrate large amounts of Cd2+. Dump sites for toxic waste contain Ni2+-Cd2+ batteries; these metals often leach into the groundwater, ultimately entering the human food chain. Cd2+ is ranked seventh among the “Top 20 Hazardous Substances Priority List” by the Agency for Toxic Substances and Disease Registry and the U.S. Environmental Protection Agency (Fay and Mumtaz, 1996). People at highest risk for Cd2+-induced lung cancer and chronic nephropathy include cigarette smokers, women having low body-iron stores, persons on a habitual diet rich in high-fiber foods or contaminated shellfish, and malnourished populations (Jarup et al., 1998; Jarup, 2002, 2003; Waalkes, 2003). For the past 80 years, Cd2+ uptake into mammalian cells has been presumed to take place before Cd2+-mediated disease can occur. One possibility for Cd2+ influx into mammalian cell cultures is by way of Ca2+ channels (Shibuya and Douglas, 1992; Hinkle and Osborne, 1994; Olivi and Bressler, 2000; Bergeron and Jumarie, 2006). SLC11A2 has a preference for Fe2+ but also transports Pb2+ and Cd2+ (Bressler et al., 2004); for this transporter, Cd2+ influx is proton-dependent (Bressler et al., 2004). Using SLC11A2 knockdown studies in human intestinal Caco-2 cells (Bannon et al., 2003), proton-dependent Cd2+ transport has been demonstrated. Other studies have suggested that SLC11A2 participates in Cd2+ transport in gastrointestinal enterocytes (Elisma and Jumarie, 2001; Tallkvist et al., 2001; Park et al., 2002) and renal distal tubular cells (Olivi et al., 2001; Park et al., 2002). Consistent with these studies, Cd2+ transport in Xenopus laevis oocytes expressing human SLC11A2 shows Michaelis-Menten kinetics with a Km of 1.04 ± 0.13 μM (Okubo et al., 2003). Still, no definitive genotype-phenotype association (i.e., a particular gene attributed to Cd2+-induced disease) was reported until 2005. Recent studies have shown such a relationship: allelic differences in the mouse Slc39a8 gene are responsible for striking variability in risk of Cd2+-induced testicular necrosis among different inbred mouse strains (Dalton et al., 2005), as well as Cd2+-induced acute renal failure (Wang et al., 2007). Slc39a8 encodes the ZIP8 transporter, which undoubtedly also transports an essential divalent cation. Although Mn2+ was shown to be the best inhibitor of ZIP8-mediated Cd2+ uptake and has a very low Km value for ZIP8-mediated uptake (2.2 μM) (He et al., 2006), we believe that zinc (Zn2+) cannot be ruled out as a substrate for ZIP8. Indeed, in studies with X. laevis oocytes (Liu et al., 2008), Km values for Cd2+ and Zn2+ were recently shown to be ∼0.48 and ∼0.26 μM, respectively. Cd2+ probably displaces Mn2+ or Zn2+ and operates as a rogue hitchhiker, entering cells via ZIP8 and subsequently contributing to cell death, cancer, and other diseases (He et al., 2006; Wang et al., 2007). The ZIP8 transporter is a metal/bicarbonate symporter (He et al., 2006). ZIP8 is localized on apical surfaces (He et al., 2006) of several cell types: between the blood and vascular endothelial cells of the testis (Dalton et al., 2005; Wang et al., 2007), and between the glomerular filtrate and proximal tubular epithelial cells of the kidney (Wang et al., 2007). ZIP8 therefore seems to act as a “gatekeeper” for maintaining intracellular Zn2+ and perhaps Mn2+ homeostasis. On the other hand, however, ZIP8 can serve as a means for bringing unwanted environmental Cd2+ into the organism. In terms of evolution, the closest neighbor to ZIP8 is ZIP14, encoded by the SLC39A14 gene. The present study provides the complete characterization of this gene and its ZIP14 mRNAs and proteins and for the first time demonstrates the significance of ZIP14 in Cd2+-mediated cell damage.