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Supplement

Integrative Aspects of Zinc Transporters^{1 ,2}

Food Science and Human Nutrition Department, University of Florida, Gainesville, FL 32611

³To whom correspondence and reprint request should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION Zinc transporter-1 Zinc transporter-2 and -3 Zinc transporter-4 Divalent cation transporter 1 Summary REFERENCES

 
Cells maintain zinc concentrations with relatively narrow limits. Nevertheless, physiologically relevant changes in free Zn(II) pools or changes in Zn bound to specific ligands or within vesicles may occur without a major change in total cellular zinc concentrations. The task of maintaining such levels rests in part with zinc transporter proteins. The genes for some putative zinc transporters have recently been cloned. As of this time, most have not been directly shown to transport zinc in functional studies, albeit evidence is strong that they have such a function. Zinc transporter (ZnT)-1 was identified as a rescue agent for cells maintained in very high extracellular zinc conditions; therefore, ZnT-1 has been suggested to function as an exporter. ZnT-1 is expressed in a variety of tissues, including intestine, kidney and liver. Intestinal expression is regional, being much greater in duodenum and jejunum and in villus versus crypt cells. Immunolocalization places ZnT-1 at the basolateral membrane of intestinal enterocytes and epithelial cells of the distal renal tubules. Regulation of ZnT-1 mRNA and ZnT-1 protein does not change markedly with changes in dietary zinc level except when a large single oral zinc supplement is provided. ZnT-1 is induced by transient ischemia of the forebrain. ZnT-2 and ZnT-3 may function in tissue-specific vesicular zinc transport. ZnT-4 is believed to be abundant in mammary gland and may be associated with zinc secretion into milk. A mutation of the ZnT-4 gene may account for the lethal milk (lm) syndrome. The putative zinc transporters identified thus far appear to have characteristics commensurate with functions in integrative zinc acquisition and homeostasis.

KEY WORDS: • zinc • metal transporters • transport • regulation • trace elements

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Zinc transporter-1 Zinc transporter-2 and -3 Zinc transporter-4 Divalent cation transporter 1 Summary REFERENCES

 
Cellular transport characteristics for various divalent cations have been well described in terms of kinetics, and to some extent, the physiologic factors regulating these kinetics have been identified. Of the nutritionally relevant minerals, the transport of calcium and its regulation by calcitriol have received the most attention. Trace element transport has received considerably less attention. Nevertheless, there is general consensus on some parameters of transport, particularly kinetics at divergent dietary intake levels and interactions among minerals present in the diet.

Zinc ions are hydrophilic and do not cross cell membranes by passive diffusion. Mechanisms to circumvent this situation have evolved. Membrane transport characteristics have been studied with various isolated cell systems, with most studies focused on intestinal uptake. The latter include perfused intestines and ligated intestinal loops (Cousins 1989 ). In general, transport has been described as having both saturable and nonsaturable components, depending on the Zn(II) concentrations involved. In addition, zinc transport exhibits time, pH, temperature and, perhaps, sulfhydryl dependency. These characteristics have been reviewed in detail (Reyes 1996 ). However, there are considerable differences in how zinc transport would be handled from a mechanistic perspective (Ripa and Ripa 1995 ). Energy dependency for Zn(II) transport remains unclear. Also to be resolved is the nature of the ligand from which Zn(II) is exchanged at the cell surface. The extent of transport appears to be rapid. For example, zinc transport and accumulation by isolated rat hepatocytes are such that there is an apparent turnover of total cell zinc in 30 h (Pattison and Cousins 1986 ).

Dietary zinc is presented to the enterocyte, as a constituent of a variety of molecules, including peptides and nucleotides of varying binding affinities. It is generally assumed that an intraluminal transition occurs that allows zinc to be transported across enterocytes as the free ion. Similarly, although albumin is the principal zinc carrier in plasma, some plasma proteins and free amino acids, which represent a rather small but consistent pool of zinc in plasma, may influence zinc delivery to cells.

A substantial advance toward our understanding of all aspects of zinc transport has developed through the cloning of genes for putative zinc transporters. Mammalian zinc transporters ZnT-1, -2, -3 and -4⁴ are among those that have been cloned, as has an iron transporter [divalent cation transporter-1 (DCT-1); Nramp2] that also exhibits zinc transport capabilities. Our present knowledge of these zinc transporters and how they can be placed within an integrative view of zinc physiology is briefly reviewed here. These transporters may be members of the cation diffusion facilitator family of proteins (Paulsen and Saier 1997 ) and have been reviewed by McMahon and Cousins (1998a) .

	Zinc transporter-1

TOP ABSTRACT INTRODUCTION Zinc transporter-1 Zinc transporter-2 and -3 Zinc transporter-4 Divalent cation transporter 1 Summary REFERENCES

 
ZnT-1 was the first zinc transporter cloned. Palmiter and Findley (1995) identified the protein in mutagenized baby hamster kidney (BHK) cells that could grow in very high extracellular zinc concentrations (300 µmol/L). Furthermore, transfection of ZnT-1 cDNA was able to rescue normal BHK cells from high extracellular zinc. Because the intracellular zinc concentrations remained low under these conditions, based on expression of a reporter gene with multiple metal response elements in the promoter, an export function for ZnT-1 was proposed. Rat cDNA for ZnT-1 predicts a protein of 507 amino acids, including a Gly-His–rich intracellular loop. There are six membrane-spanning domains with both the N and C termini residing intracellularly. The significance of the intracellular histidine-rich domain is not clear. However, similar domains in metal transporters or trafficking proteins suggest a role in chelation or acidification related to these processes. Activity of this transporter in BHK cells was insensitive to azide and cyanide, suggesting energy production was not required. The latter is generally not the situation reported for zinc uptake by cells (Failla and Cousins 1978 , Reyes 1996 ). ZnT-1–related efflux did not require a sodium gradient. Palmiter and Findley (1995) provided evidence suggesting that the first two membrane-spanning domains and the C-terminal region are essential for the enhanced zinc resistance in BHK cells that ZnT-1 provides. ZnT-1 also has sites for glycosylation, phosphorylation and post-translational processing. Expression of ZnT-1 as a fluorescent fusion protein showed localization to the plasma membrane of zinc-resistant BHK cells. This convincingly supports an exporter function for ZnT-1 under some conditions.

Cells do not confront extremely high zinc concentrations under physiologic conditions. Consequently, because ZnT-1 was identified in cultured cells under such conditions, experiments in animals have been carried out to evaluate the physiologic relevance of ZnT-1. The first such evidence was derived from differential display polymerase chain reaction screening of mRNAs up-regulated during transient forebrain ischemia in gerbils (Tsuda et al. 1997 ). One mRNA was identified as the gerbil homolog of rat ZnT-1. The up-regulation of ZnT-1 was related to neuronal death, a phenomenon that follows zinc influx into these cells. The concept of the neurotoxicity of zinc was advanced by Koh et al. (1996) . Furthermore, fetal rat hippocampal neurons in primary culture had transiently increased ZnT-1 mRNA levels when exposed to very high zinc concentrations (150 µmol/L). These findings suggest that increased ZnT-1 expression could be a defense mechanism to delay zinc-related neuronal damage by increasing zinc efflux from the ischemic cells of intact brain.

Our approach to address transporter function has been to measure the expression of these proteins within the context of physiologically induced metabolic shifts in zinc trafficking within intact animals. Initial experiments were performed with ZnT-1 but have now been extended to include other ZnTs. Rat ZnT-1 cDNA was produced from rat intestinal mRNA by reverse transcriptase-polymerase chain reaction that represented 737 bp of the kidney ZnT-1. This cDNA showed low homology to other ZnTs (Palmiter et al. 1996a ). Two transcripts are observed on Northern blot analysis (McMahon and Cousins 1998b ). This may reflect processing characteristics and coincides with reports of multiple transcripts reported for other transporter mRNAs. Two transcripts have been reported for human ZnT-1 mRNA (Fuse et al. 1997 ). In addition, a rabbit polyclonal antibody was generated against a ZnT-1 peptide and affinity purified (McMahon and Cousins 1998b ). The peptide sequence corresponded to the C-terminal end of ZnT-1. ZnT-1 protein gave strong signals by Western blotting with membrane protein preparations from intestine and liver. Regional distribution of ZnT-1 was in proximal intestine (duodenum and jejunum) with little in distal intestine. Furthermore, virtually no ZnT-1 expression was observed in crypt cells compared with villus cells. This pattern suggests a role in zinc absorption but could also relate to zinc loss (excretion) into the intestinal lumen. Immunofluorescence microscopy defined ZnT-1 orientation to the basolateral surface of enterocytes with no expression in goblet cells or those in the lamina propria. This orientation is consistent with a function related to zinc efflux into the portal circulation with body zinc accumulation as a physiologic outcome (McMahon and Cousins 1998b ). Similarly, ZnT-1 localization was at the basolateral membrane of renal tubular cells (McMahon and Cousins 1998a ), particularly those lining the thick ascending and distal convoluted tubules (Fig. 1 ). Localization is similar to that reported for Na⁺,K⁺-ATPase that provides energy for Na⁺ reabsorption. This finding is highly relevant because urine is not a major route of zinc secretion, and this conservation mechanism for zinc results from the major reabsorptive capacity that the kidney has for this mineral (Victery et al. 1981 ).

View larger version (69K): [in this window] [in a new window]   Figure 1. Immunofluorescence localization of ZnT-1 transporter at the basolateral membrane of renal tubular cells of rat kidney. Affinity-purified IgG against a peptide from the N-terminal end of rat ZnT-1 was the primary antibody. Fluorescence (red) was developed with Alexa anti-IgG conjugate (Molecular Probes, Eugene, OR) as the secondary antibody. DAPI is the blue fluorescence used to identify nuclei. Panel A: An oblique section through the cortex shows ZnT-1 localization (arrow) to the cells lining the distal convoluted tubule. Panel B: An oblique section through the outer medulla shows ZnT-1 localization (arrow) to the cells lining the thick ascending limb of the nephron. (x400.)

It may also be relevant that ZnT-1 was discovered in cells that had been engineered for resistance to zinc concentrations that are lethal to normal cells. In this regard, it is of interest that, after a wide range of cell lines in culture were screened, none have been found to express ZnT-1 protein.

Up-regulation of intestinal and liver ZnT-1 was examined in metallothionein transgenic (overexpression) and null (no expression) mouse strains, using an oral zinc load as the stimulus for altered zinc metabolism because metallothionein appears to alter the intracellular processing of zinc (Davis et al. 1998 ). Marked increases in ZnT-1 mRNA were found in both liver and intestine after the zinc dose. In this regard, mice respond to a greater extent than rats with the same dose (0.5 mmol Zn/kg) used in the experiments with rats discussed earlier. However, the capacity to produce metallothionein did not appear to influence the response of ZnT-1 to zinc administration.

ZnT-1 has a wide tissue distribution in the rodent models examined. It should be pointed out that cells within the intestinal lamina propria and goblet cells, and many renal cells, do not express detectable amounts of ZnT-1; thus, expression is not ubiquitous (McMahon and Cousins 1998a , 1998b ). We detected extensive ZnT-1 expression in rat placenta extending from at least d 8 of gestation. As shown in Figure 2 , strong immunofluorescence demonstrates ZnT-1 is localized in the villus yolk sac of a d-18 rat placenta. These cells are most likely those associated with the transport of nutrients to the fetus based on localization of amino acid transporters in the same cellular localization at this gestational age (Matthews et al. 1998 ). These localization results suggest that ZnT-1 could be very important for fetal zinc nutriture. The lethality of the ZnT-1 knockout early in gestation also supports such a role for fetal zinc acquisition and retention.

View larger version (44K): [in this window] [in a new window]   Figure 2. Immunofluorescence localization of ZnT-1 transporter localized to the villus yolk sac of d-18 rat placenta. Affinity-purified IgG against a peptide from the N-terminal end of rat ZnT-1 was the primary antibody. Fluorescence (red) was developed with Alexa anti-IgG conjugate (Molecular Probes) as the secondary antibody. DAPI is the blue fluorescence used to identify nuclei. A cross section is shown with ZnT-1 fluorescence in cells lining these placental villi (arrow). (x630.)

	Zinc transporter-2 and -3

TOP ABSTRACT INTRODUCTION Zinc transporter-1 Zinc transporter-2 and -3 Zinc transporter-4 Divalent cation transporter 1 Summary REFERENCES

The distribution of ZnT-3 may be limited to brain and testis, with a vesicular transporter as its most likely role in zinc physiology. The vesicular packaging of zinc in synaptic signaling is very likely important for neuronal function. As a result, ZnT-3 may eventually be shown to have a role in neurodegenerative function/diseases and spermatogenesis (Palmiter et al. 1996b ). The relationship of ZnT-3 to the physiology of zinc in synaptic vesicles and male reproduction has yet to be investigated. We previously reviewed aspects of ZnT-2 and ZnT-3 (McMahon and Cousins 1998a ).

	Zinc transporter-4

TOP ABSTRACT INTRODUCTION Zinc transporter-1 Zinc transporter-2 and -3 Zinc transporter-4 Divalent cation transporter 1 Summary REFERENCES

 
The identification of ZnT-4 resulted from positional cloning experiments to describe the murine pallid mutation (Huang and Gitschier 1997 ). The protein has characteristics that support a zinc transporter function (reviewed in McMahon and Cousins 1998b ). A single-point mutation in ZnT-4 was found to result in the lethal mouse (lm) syndrome described two decades ago (Piletz and Ganschow 1978 ). The lm syndrome is characterized by pups that do not survive when nursed by lactating dams with the lm genotype. Pups develop normally when nursed by non-lm dams or if they are administered zinc orally (Ackland and Mercer 1992 ). Lee et al. (1992) demonstrated that the lm mutation results in markedly less zinc secretion into the milk. Presumably, this is due to a reduction in ZnT-4 transporter activity and retention of zinc within the mammary gland. Although Huang and Gitschier (1997) have not tested ZnT-4 expression in mammary gland of lm mice, the transporter is expressed in two murine mammary cell lines. ZnT-4 was expressed in liver, lung, kidney, spleen, heart and brain; the latter displayed the greatest ZnT-4 mRNA levels on Northern blot analysis. The transporter function for ZnT-4 is based on homology to murine ZnT-2 and ZnT-3 and that it confers zinc resistance when the murine ZnT-4 cDNA is used to transform zinc-sensitive yeast. A rat homolog for murine ZnT-4 has been termed Dri 27. It was identified as a developmentally regulated intestinal gene (Murgia et al. 1999 ).

	Divalent cation transporter 1

TOP ABSTRACT INTRODUCTION Zinc transporter-1 Zinc transporter-2 and -3 Zinc transporter-4 Divalent cation transporter 1 Summary REFERENCES

 
A transporter that functions in the transport of a number of cations has been cloned (Gunshin et al. 1997 ). This transporter, DCT1, is also called Nramp2 (Fleming et al. 1998 ), and it appears to be essential for iron absorption. DCT1 is up-regulated by the iron-deficient state. Functional studies carried out with Xenopus oocytes using mRNA injections show transport affinity that is as high for zinc as it is for iron. Although this transporter protein is distinctly different from the ZnT molecules, its apparent ability to transport zinc is of interest because numerous studies have shown that a low iron intake enhances the intestinal absorption of zinc (reviewed in Solomons 1983 ). Therefore, up-regulation of DCT1 in response to low iron status but without additional iron in the intestinal lumen may cause more zinc to be absorbed because the affinities for both cations are similar. No integrative studies on DCT1 as regulated by zinc have been carried out.

	Summary

TOP ABSTRACT INTRODUCTION Zinc transporter-1 Zinc transporter-2 and -3 Zinc transporter-4 Divalent cation transporter 1 Summary REFERENCES

 
Zinc transporters located on the plasma membrane of cells and with intracellular vesicles undoubtedly influence zinc metabolism and help account for the ability of this micronutrient to adapt to extremes of intake from the dietary supply. There is a clear difference in transporter levels when expression is based on immunologically reactive protein rather than on mRNA abundance changes. The data obtained to date suggest that the expression of at least some zinc transporters is regulated by the physiologic and nutritional status of animals. Our understanding of the integrative importance of these transporters will expand our understanding of the biochemical roles of zinc in animals.

	FOOTNOTES

 
¹ Presented at the international workshop "Zinc and Health: Current Status and Future Directions," held at the National Institutes of Health in Bethesda, MD, on November 4–5, 1998. This workshop was organized by the Office of Dietary Supplements, NIH and cosponsored with the American Dietetic Association, the American Society for Clinical Nutrition, the Centers for Disease Control and Prevention, Department of Defense, Food and Drug Administration/Center for Food Safety and Applied Nutrition and seven Institutes, Centers and Offices of the NIH (Fogarty International Center, National Institute on Aging, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Drug Abuse, National Institute of General Medical Sciences and the Office of Research on Women’s Health). Published as a supplement to The Journal of Nutrition. Guest editors for this publication were Michael Hambidge, University of Colorado Health Sciences Center, Denver; Robert Cousins, University of Florida, Gainesville; Rebecca Costello, Office of Dietary Supplements, NIH, Bethesda, MD; and session chair, Bo Lönnerdal, University of California at Davis.

² Supported by National Institutes of Health Grant DK 31127 (to RJC), Institutional National Research Service Award DK07667, Individual National Research Service Award DK09628 (to R.J.M.) and Boston Family Endowment Funds of the University of Florida. Experiments with animals from the authors’ laboratory described in this review follow the guidelines of University of Florida Institutional Animal Care and Use Committee.

⁴ Abbreviations used: BHK, baby hamster kidney; DCT, divalent cation transporter; ZnT, zinc transporter.

	REFERENCES

TOP ABSTRACT INTRODUCTION Zinc transporter-1 Zinc transporter-2 and -3 Zinc transporter-4 Divalent cation transporter 1 Summary REFERENCES

 

1. Ackland M. L., Mercer J.F.B. The murine mutation, lethal milk, results in production of zinc deficient milk. J. Nutr. 1992;122:1214-1218

2. Cousins R. J. Theoretical and practical aspects of zinc uptake and absorption. Laszlo J. A. Dintzis F. R. eds. Mineral Absorption in the Monogastric GI Tract: Chemical, Nutritional and Physiological Aspects 1989:3-12 Plenum Publishing Corporation New York, NY.

3. da Silva J.J.R., Williams R.J.P. The Biological Chemistry of the Elements: The Inorganic Chemistry of Life 1991 Clarendon Press Oxford.

4. Davis S. R., McMahon R. J., Cousins R. J. Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc-dependent zinc transporter-1 (ZnT-1) expression. J. Nutr. 1998;128:825-831[Abstract/Free Full Text]

5. Failla M. L., Cousins R. J. Zinc accumulation and metabolism in primary cultures of rat liver cells: regulation by glucocorticoids. Biochim. Biophys. Acta 1978;543:293-304[Medline]

6. Fleming M. D., Romano M. A., Su M. A., Garrick L. M., Garrick M. D., Andrews N. C. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc. Natl. Acad. Sci. U.S.A. 1998;95:1148-1153[Abstract/Free Full Text]

7. Fuse Y., Morishima T., Esumi M. Cloning and sequence analysis of human zinc transporter (ZnT-1) cDNA. FASEB J 1997;11:A970

8. Gunshin H., Mackenzie B., Berger U. V., Gunshin Y., Romero M. F., Boron W. F., Nussberger S., Gollan J. L., Hediger M. A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature (Lond.) 1997;388:482-488[Medline]

9. Huang L., Gitschier J. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat. Genet. 1997;17:292-297[Medline]

10. Koh J.-Y., Suh S. W., Gwag B. J., He Y. Y., Hsu C. Y., Choi D. W. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science (Washington DC) 1996;272:1013-1016[Abstract]

11. Lee D. Y., Shay N. F., Cousins R. J. Altered zinc metabolism occurs in murine lethal milk syndrome. J. Nutr. 1992;122:2233-2238

12. Matthews J. C., Beveridge M. J., Malandro M. S., Rothstein J. D., Campbell-Thompson M., Verlander J. W., Kilberg M. S., Novak D. A. Activity and protein localization of multiple glutamate transporters in gestation day 14 vs. day 20 rat placenta. Am. J. Physiol. 1998;274:C603-C614[Abstract/Free Full Text]

13. McMahon R. J., Cousins R. J. Mammalian zinc transporters. J. Nutr. 1998a;128:667-670[Abstract/Free Full Text]

14. McMahon R. J., Cousins R. J. Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc. Natl. Acad. Sci. U.S.A. 1998b;95:4841-4846[Abstract/Free Full Text]

15. Murgia C., Vespignani I., Cerase J., Nobili F., Perozzi G. Cloning, expression, and vesicular localization of zinc transporter DRI 27/ZnT4 in intestinal tissue and cells. Am. J. Physiol. 1999;277:G1231-G1239[Abstract/Free Full Text]

16. Palmiter R. D., Cole T. B., Findley S. D. ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO J 1996a;15:1784-1791[Medline]

17. Palmiter R. D., Cole T. B., Quaife C. J., Findley S. D. ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc. Natl. Acad. Sci. U.S.A. 1996b;93:14934-14939[Abstract/Free Full Text]

18. Palmiter R. D., Findley S. D. Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J 1995;14:639-649[Medline]

19. Pattison S. E., Cousins R. J. Kinetics of zinc uptake and exchange by primary cultures of rat hepatocytes. Am. J. Physiol. 1986;250:E677-E685[Abstract/Free Full Text]

20. Paulsen I. T., Saier M. H., Jr A novel family of ubiquitous heavy metal ion transport proteins. J. Membr. Biol. 1997;156:99-103[Medline]

21. Piletz J. E., Ganschow R. E. Zinc deficiency in murine milk underlies expression of the lethal milk mutation. Science (Washington DC) 1978;199:181-183[Abstract/Free Full Text]

22. Reyes J. G. Zinc transport in mammalian cells. Am. J. Physiol. 1996;270:C401-C410[Abstract/Free Full Text]

23. Ripa S., Ripa R. Zinc cellular traffic: physiopathological considerations. Minerva Med 1995;86:37-43[Medline]

24. Solomons N. W. Competitive mineral-mineral interaction in the intestine: implications for zinc absorption in humans. Inglett G. E. eds. Nutritional Bioavailability of Zinc 1983:247-272 American Chemical Society Washington, DC.

25. Suhy D. A., O’Halloran T. V. Metal-responsive gene regulation and the zinc metalloregulatory model. Met. Ions Biol. Syst. 1996;32:557-578[Medline]

26. Tsuda M., Imaizumi K., Katayama T., Kitagawa K., Wanaka A., Tohyama M., Takagi T. Expression of zinc transporter gene, ZnT-1, is induced after transient forebrain ischemia in the gerbil. J. Neurosci. 1997;17:6678-6684[Abstract/Free Full Text]

27. Victery W., Smith J. M., Vander A. J. Renal tubular handling of zinc in the dog. Am. J. Physiol. 1981;241:F532-F539[Medline]

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