, Volume 23, Issue 5, pp 857–875 | Cite as

Catch me if you can! Novel aspects of cadmium transport in mammalian cells

  • Frank ThévenodEmail author


Cadmium (Cd2+) is a nonessential divalent metal ion that causes toxicity in multiple organs in humans. In order for toxicity to occur Cd2+ must first enter cells by utilizing transport pathways for essential metals. This review focuses on studies in which Cd2+ transport was directly demonstrated by electrophysiological, radiotracer or Cd2+-sensitive fluorescent dye techniques. The chemistry of Cd2+ and metal ions in general is addressed in the context of properties relevant for transport through membrane proteins, such as hydration energy. Apart from transport by the ZIP transporters SLC39A8 and SLC39A14, which is not topic of the review, uptake of free Cd2+ has been demonstrated for the Fe2+/H+ cotransporter divalent metal transporter 1. Moreover, the multiligand endocytic receptors megalin and cubilin take up cadmium-metallothionein complexes via receptor-mediated endocytosis. The role of ATP binding cassette transporters in Cd2+ efflux from cells is also discussed. Both the multidrug resistance-associated protein 1 and cystic fibrosis transmembrane conductance regulator are likely to transport cadmium–glutathione complexes out of cells, whereas transport of free Cd2+ by the multidrug resistance P-glycoprotein remains controversial. Finally, arguments for and against Cd2+ transport by Ca2+ channels are presented. Most N- and L-type Ca2+ channels are closed at resting membrane potential (with the exception of CaV1.3 channels) and therefore unlikely to allow significant Cd2+ influx under physiological conditions. CaV3.1 and CaV3.2 T-type calcium channels are permeated by divalent metal ions, such as Fe2+ and Mn2+ because of considerable “window” currents close to resting membrane potential and could be responsible for tonic Cd2+ entry. TRPM7 and the mitochondrial Ca2+ uniporter are other likely candidates for Cd2+ transporters, whereas the role of Orai proteins, the store-operated calcium channels carrying Ca2+ release-activated Ca2+ current, in Cd2+ influx remains to be investigated.


Calcium channels ABC transporters Standard enthalpy of hydration 24p3/NGAL/lipocalin-2 receptor Epithelial transport 



I would like to thank Drs. Stephen W. Jones (Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH,USA), Bryan Mackenzie (Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA) and Reinhold Penner (Center for Biomedical Research, The Queen’s Medical Center, Honolulu, HI, USA) for valuable discussions and for sharing unpublished data, my collaborators Drs. Marouan Abouhamed, Wing-Kee Lee and Natascha A. Wolff, and the Deutsche Forschungsgemeinschaft (TH 345/8-1, 10-1 and 11-1) for financial support.


  1. Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906–19912PubMedCrossRefGoogle Scholar
  2. Abouhamed M, Gburek J, Liu W et al (2006) Divalent metal transporter 1 in the kidney proximal tubule is expressed in late endosomes/lysosomal membranes: implications for renal handling of protein-metal complexes. Am J Physiol Renal Physiol 290:F1525–F1533PubMedCrossRefGoogle Scholar
  3. Abouhamed M, Wolff NA, Lee WK et al (2007) Knockdown of endosomal/lysosomal divalent metal transporter 1 by RNA interference prevents cadmium-metallothionein-1 cytotoxicity in renal proximal tubule cells. Am J Physiol Renal Physiol 293:F705–F712PubMedCrossRefGoogle Scholar
  4. Achard-Joris M, van Saparoea HB, Driessen AJ et al (2005) Heterologously expressed bacterial and human multidrug resistance proteins confer cadmium resistance to Escherichia coli. Biochemistry 44:5916–5922PubMedCrossRefGoogle Scholar
  5. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE et al (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22:7468–7485PubMedCrossRefGoogle Scholar
  6. Andersen O (1984) Chelation of cadmium. Environ Health Perspect 54:249–266PubMedCrossRefGoogle Scholar
  7. Andreasen D, Jensen BL, Hansen PB et al (2000) The alpha(1G)-subunit of a voltage-dependent Ca(2 +) channel is localized in rat distal nephron and collecting duct. Am J Physiol Renal Physiol 279:F997–F1005PubMedGoogle Scholar
  8. Annereau JP, Ko YH, Pedersen PL (2003) Cystic fibrosis transmembrane conductance regulator: the NBF1+R (nucleotide-binding fold 1 and regulatory domain) segment acting alone catalyses a Co2+/Mn2+/Mg2+-ATPase activity markedly inhibited by both Cd2+ and the transition-state analogue orthovanadate. Biochem J 371:451–462PubMedCrossRefGoogle Scholar
  9. ATSDR (2005) Agency for toxic substance and disease registry, U.S. Toxicological Profile for Cadmium. Department of Health and Humans Services, Public Health Service, Centers for Disease Control, Atlanta, GA, USAGoogle Scholar
  10. Bannon DI, Abounader R, Lees PS et al (2003) Effect of DMT1 knockdown on iron, cadmium, and lead uptake in Caco-2 cells. Am J Physiol Cell Physiol 284:C44–C50PubMedGoogle Scholar
  11. Barbier O, Jacquillet G, Tauc M et al (2004) Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo. Am J Physiol Renal Physiol 287:F1067–F1075PubMedCrossRefGoogle Scholar
  12. Bernard A, Buchet JP, Roels H et al (1979) Renal excretion of proteins and enzymes in workers exposed to cadmium. Eur J Clin Invest 9:11–22PubMedCrossRefGoogle Scholar
  13. Bernard AM, Ouled Amor A, Lauwerys RR (1987) The effects of low doses of cadmium-metallothionein on the renal uptake of beta 2-microglobulin in rats. Toxicol Appl Pharmacol 87:440–445PubMedCrossRefGoogle Scholar
  14. Bird GS, DeHaven WI, Smyth JT et al (2008) Methods for studying store-operated calcium entry. Methods 46:204–212PubMedCrossRefGoogle Scholar
  15. Blazka ME, Shaikh ZA (1991) Differences in cadmium and mercury uptakes by hepatocytes: role of calcium channels. Toxicol Appl Pharmacol 110:355–363PubMedCrossRefGoogle Scholar
  16. Bose S, Kalra S, Yammani RR et al (2007) Plasma membrane delivery, endocytosis and turnover of transcobalamin receptor in polarized human intestinal epithelial cells. J Physiol 581:457–466PubMedCrossRefGoogle Scholar
  17. Bridges CC, Zalups RK (2005) Molecular and ionic mimicry and the transport of toxic metals. Toxicol Appl Pharmacol 204:274–308PubMedCrossRefGoogle Scholar
  18. Buckett PD, Wessling-Resnick M (2009) Small molecule inhibitors of divalent metal transporter-1. Am J Physiol Gastrointest Liver Physiol 296:G798–G804PubMedCrossRefGoogle Scholar
  19. Bullen JJ, Rogers HJ, Spalding PB et al (2005) Iron and infection: the heart of the matter. FEMS Immunol Med Microbiol 43:325–330PubMedCrossRefGoogle Scholar
  20. Canonne-Hergaux F, Gros P (2002) Expression of the iron transporter DMT1 in kidney from normal and anemic mk mice. Kidney Int 62:147–156PubMedCrossRefGoogle Scholar
  21. Canonne-Hergaux F, Gruenheid S, Ponka P et al (1999) Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 93:4406–4417PubMedGoogle Scholar
  22. Carvou N, Norden AG, Unwin RJ et al (2007) Signalling through phospholipase C interferes with clathrin-mediated endocytosis. Cell Signal 19:42–51PubMedCrossRefGoogle Scholar
  23. Childers M, Eckel G, Himmel A et al (2007) A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates. Med Hypotheses 68:101–112PubMedCrossRefGoogle Scholar
  24. Chin KV, Tanaka S, Darlington G et al (1990) Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. J Biol Chem 265:221–226PubMedGoogle Scholar
  25. Chow RH (1991) Cadmium block of squid calcium currents. Macroscopic data and a kinetic model. J Gen Physiol 98:751–770PubMedCrossRefGoogle Scholar
  26. Christensen EI, Birn H (2002) Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 3:256–266PubMedGoogle Scholar
  27. Christensen EI, Gburek J (2004) Protein reabsorption in renal proximal tubule-function and dysfunction in kidney pathophysiology. Pediatr Nephrol 19:714–721PubMedCrossRefGoogle Scholar
  28. Clarkson TW (1993) Molecular and ionic mimicry of toxic metals. Annu Rev Pharmacol Toxicol 33:545–571PubMedCrossRefGoogle Scholar
  29. Crawford I, Maloney PC, Zeitlin PL et al (1991) Immunocytochemical localization of the cystic fibrosis gene product CFTR. Proc Natl Acad Sci USA 88:9262–9266PubMedCrossRefGoogle Scholar
  30. Dalton TP, He L, Wang B et al (2005) Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proc Natl Acad Sci USA 102:3401–3406PubMedCrossRefGoogle Scholar
  31. Deeley RG, Westlake C, Cole SP (2006) Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev 86:849–899PubMedCrossRefGoogle Scholar
  32. Deng X, Wang Y, Zhou Y et al (2009) STIM and Orai: dynamic intermembrane coupling to control cellular calcium signals. J Biol Chem 284:22501–22505PubMedCrossRefGoogle Scholar
  33. Devireddy LR, Teodoro JG, Richard FA et al (2001) Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science 293:829–834PubMedCrossRefGoogle Scholar
  34. Devireddy LR, Gazin C, Zhu X et al (2005) A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123:1293–1305PubMedCrossRefGoogle Scholar
  35. Diaz D, Bartolo R, Delgadillo DM et al (2005) Contrasting effects of Cd2+ and Co2+ on the blocking/unblocking of human Cav3 channels. J Membr Biol 207:91–105PubMedCrossRefGoogle Scholar
  36. Diebler HM, Eigen M, Ilgenfritz G et al (1969) Kinetics and mechanism of reactions of main group metal ions with biological carriers. Pure Appl Chem 20:93–115CrossRefGoogle Scholar
  37. Donovan A, Brownlie A, Zhou Y et al (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781PubMedCrossRefGoogle Scholar
  38. Dorian C, Gattone VH II, Klaassen CD (1992a) Accumulation and degradation of the protein moiety of cadmium-metallothionein (CdMT) in the mouse kidney. Toxicol Appl Pharmacol 117:242–248PubMedCrossRefGoogle Scholar
  39. Dorian C, Gattone VH II, Klaassen CD (1992b) Renal cadmium deposition and injury as a result of accumulation of cadmium-metallothionein (CdMT) by the proximal convoluted tubules: a light microscopic autoradiography study with 109CdMT. Toxicol Appl Pharmacol 114:173–181PubMedCrossRefGoogle Scholar
  40. Edsall JT, McKenzie HA (1978) Water and proteins. I. The significance and structure of water; its interaction with electrolytes and non-electrolytes. Adv Biophys 10:137–207PubMedGoogle Scholar
  41. El-Annan J, Brown D, Breton S et al (2004) Differential expression and targeting of endogenous Arf1 and Arf6 small GTPases in kidney epithelial cells in situ. Am J Physiol Cell Physiol 286:C768–C778PubMedCrossRefGoogle Scholar
  42. Endo T, Kimura O, Sakata M (2002) Effects of P-glycoprotein inhibitors on cadmium accumulation in cultured renal epithelial cells, LLC-PK1, and OK. Toxicol Appl Pharmacol 185:166–171PubMedCrossRefGoogle Scholar
  43. Erfurt C, Roussa E, Thévenod F (2003) Apoptosis by Cd2+ or CdMT in proximal tubule cells: different uptake routes and permissive role of endo/lysosomal CdMT uptake. Am J Physiol Cell Physiol 285:C1367–C1376PubMedGoogle Scholar
  44. Fasolato C, Hoth M, Penner R (1993) Multiple mechanisms of manganese-induced quenching of fura-2 fluorescence in rat mast cells. Pflugers Arch 423:225–231PubMedCrossRefGoogle Scholar
  45. Ferguson CJ, Wareing M, Ward DT et al (2001) Cellular localization of divalent metal transporter DMT-1 in rat kidney. Am J Physiol Renal Physiol 280:F803–F814PubMedGoogle Scholar
  46. Feske S, Gwack Y, Prakriya M et al (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185PubMedCrossRefGoogle Scholar
  47. Fleming MD, Romano MA, Su MA et al (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95:1148–1153PubMedCrossRefGoogle Scholar
  48. Flo TH, Smith KD, Sato S et al (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917–921PubMedCrossRefGoogle Scholar
  49. Friedman PA, Gesek FA (1994) Cadmium uptake by kidney distal convoluted tubule cells. Toxicol Appl Pharmacol 128:257–263PubMedCrossRefGoogle Scholar
  50. Garrick MD, Singleton ST, Vargas F et al (2006) DMT1: which metals does it transport? Biol Res 39:79–85PubMedCrossRefGoogle Scholar
  51. Ghio AJ, Turi JL, Madden MC et al (2007) Lung injury after ozone exposure is iron dependent. Am J Physiol Lung Cell Mol Physiol 292:L134–L143PubMedCrossRefGoogle Scholar
  52. Girijashanker K, He L, Soleimani M et al (2008) Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Mol Pharmacol 73:1413–1423PubMedCrossRefGoogle Scholar
  53. Goetz DH, Holmes MA, Borregaard N et al (2002) The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell 10:1033–1043PubMedCrossRefGoogle Scholar
  54. Gottesman MM, Ling V (2006) The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett 580:998–1009PubMedCrossRefGoogle Scholar
  55. Gruenheid S, Cellier M, Vidal S et al (1995) Identification and characterization of a second mouse Nramp gene. Genomics 25:514–525PubMedCrossRefGoogle Scholar
  56. Gruenheid S, Canonne-Hergaux F, Gauthier S et al (1999) The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J Exp Med 189:831–841PubMedCrossRefGoogle Scholar
  57. Gunshin H, Mackenzie B, Berger UV et al (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488PubMedCrossRefGoogle Scholar
  58. Harrington MA, Gunderson KL, Kopito RR (1999) Redox reagents and divalent cations alter the kinetics of cystic fibrosis transmembrane conductance regulator channel gating. J Biol Chem 274:27536–27544PubMedCrossRefGoogle Scholar
  59. He L, Girijashanker K, Dalton TP et al (2006) ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol Pharmacol 70:171–180PubMedGoogle Scholar
  60. He L, Wang B, Hay EB et al (2009) Discovery of ZIP transporters that participate in cadmium damage to testis and kidney. Toxicol Appl Pharmacol 238:250–257PubMedCrossRefGoogle Scholar
  61. Hengstler JG, Bolm-Audorff U, Faldum A et al (2003) Occupational exposure to heavy metals: DNA damage induction and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous than hitherto expected. Carcinogenesis 24:63–73PubMedCrossRefGoogle Scholar
  62. Hille B (1992) Ionic channels of excitable membranes. Sinauer Associates Inc, Sunderland, MAGoogle Scholar
  63. Hinkle PM, Osborne ME (1994) Cadmium toxicity in rat pheochromocytoma cells: studies on the mechanism of uptake. Toxicol Appl Pharmacol 124:91–98PubMedCrossRefGoogle Scholar
  64. Hinkle PM, Shanshala ED II, Nelson EJ (1992) Measurement of intracellular cadmium with fluorescent dyes. Further evidence for the role of calcium channels in cadmium uptake. J Biol Chem 267:25553–25559PubMedGoogle Scholar
  65. Hobson SA, Wright J, Lee F et al (2003) Activation of the MAP kinase cascade by exogenous calcium-sensing receptor. Mol Cell Endocrinol 200:189–198PubMedCrossRefGoogle Scholar
  66. Hoth M, Penner R (1993) Calcium release-activated calcium current in rat mast cells. J Physiol 465:359–386PubMedGoogle Scholar
  67. Hryciw DH, Guggino WB (2000) Cystic fibrosis transmembrane conductance regulator and the outwardly rectifying chloride channel: a relationship between two chloride channels expressed in epithelial cells. Clin Exp Pharmacol Physiol 27:892–895PubMedCrossRefGoogle Scholar
  68. Hu J, Mao Y, White K (2002) Renal cell carcinoma and occupational exposure to chemicals in Canada. Occup Med (Lond) 52:157–164CrossRefGoogle Scholar
  69. Hughes BP, Both K, Harland L et al (1993) Identification of an mRNA species which encodes a voltage-operated Ca2+ channel in rat liver mRNA. Biochem Mol Biol Int 31:193–200PubMedGoogle Scholar
  70. Hvidberg V, Jacobsen C, Strong RK et al (2005) The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett 579:773–777PubMedCrossRefGoogle Scholar
  71. IARC (1993) Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. Working Group views and expert opinions, Lyon, 9–16 February 1993. IARC Monogr Eval Carcinog Risks Hum 58:1–415Google Scholar
  72. Iolascon A, De Falco L (2009) Mutations in the gene encoding DMT1: clinical presentation and treatment. Semin Hematol 46:358–370PubMedCrossRefGoogle Scholar
  73. Jabado N, Canonne-Hergaux F, Gruenheid S et al (2002) Iron transporter Nramp2/DMT-1 is associated with the membrane of phagosomes in macrophages and Sertoli cells. Blood 100:2617–2622PubMedCrossRefGoogle Scholar
  74. Jacobson KB, Turner JE (1980) The interaction of cadmium and certain other metal ions with proteins and nucleic acids. Toxicology 16:1–37PubMedCrossRefGoogle Scholar
  75. Jamieson Q, Obejero-Paz CA, Jones SW (2008) Mn2+ blocks, permeates, and shifts gating of CaV3.1 T-type calcium channels. Biophys J Biophys Soc Meet Abstr. Abstract # 3129Google Scholar
  76. Jarup L, Akesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238:201–208PubMedCrossRefGoogle Scholar
  77. Jayaraman A, Roberts KA, Yoon J et al (2005) Identification of neutrophil gelatinase-associated lipocalin (NGAL) as a discriminatory marker of the hepatocyte-secreted protein response to IL-1beta: a proteomic analysis. Biotechnol Bioeng 91:502–515PubMedCrossRefGoogle Scholar
  78. Jouret F, Bernard A, Hermans C et al (2007) Cystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney. J Am Soc Nephrol 18:707–718PubMedCrossRefGoogle Scholar
  79. Jurado RL (1997) Iron, infections, and anemia of inflammation. Clin Infect Dis 25:888–895PubMedCrossRefGoogle Scholar
  80. Kaku T, Lee TS, Arita M et al (2003) The gating and conductance properties of Cav3.2 low-voltage-activated T-type calcium channels. Jpn J Physiol 53:165–172PubMedCrossRefGoogle Scholar
  81. Kang HW, Park JY, Jeong SW et al (2006) A molecular determinant of nickel inhibition in Cav3.2 T-type calcium channels. J Biol Chem 281:4823–4830PubMedCrossRefGoogle Scholar
  82. Kang HW, Vitko I, Lee SS et al (2009) Structural determinants of the high affinity extracellular zinc binding site on Cav3.2 T-type calcium channels. J Biol Chem doi: 10.1074/jbc.M109.067660
  83. Kaplan JH, Lutsenko S (2009) Copper transport in mammalian cells: special care for a metal with special needs. J Biol Chem 284:25461–25465PubMedCrossRefGoogle Scholar
  84. Kim DW, Kim KY, Choi BS et al (2007) Regulation of metal transporters by dietary iron, and the relationship between body iron levels and cadmium uptake. Arch Toxicol 81:327–334PubMedCrossRefGoogle Scholar
  85. Kimura O, Endo T, Hotta Y et al (2005) Effects of P-glycoprotein inhibitors on transepithelial transport of cadmium in cultured renal epithelial cells, LLC-PK(1) and LLC-GA5-COL 150. Toxicology 208:123–132PubMedCrossRefGoogle Scholar
  86. Kippler M, Goessler W, Nermell B et al (2009) Factors influencing intestinal cadmium uptake in pregnant Bangladeshi women: a prospective cohort study. Environ Res 109:914–921PubMedCrossRefGoogle Scholar
  87. Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364PubMedCrossRefGoogle Scholar
  88. Klaassen CD, Liu J, Choudhuri S (1999) Metallothionein: an intracellular protein to protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 39:267–294PubMedCrossRefGoogle Scholar
  89. Klaassen CD, Liu J, Diwan BA (2009) Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 238:215–220PubMedCrossRefGoogle Scholar
  90. Klassen RB, Crenshaw K, Kozyraki R et al (2004) Megalin mediates renal uptake of heavy metal metallothionein complexes. Am J Physiol Renal Physiol 287:F393–F403PubMedCrossRefGoogle Scholar
  91. Knopfel M, Zhao L, Garrick MD (2005) Transport of divalent transition-metal ions is lost in small-intestinal tissue of b/b Belgrade rats. Biochemistry 44:3454–3465PubMedCrossRefGoogle Scholar
  92. Kogan I, Ramjeesingh M, Li C et al (2003) CFTR directly mediates nucleotide-regulated glutathione flux. EMBO J 22:1981–1989PubMedCrossRefGoogle Scholar
  93. Kozyraki R, Fyfe J, Verroust PJ et al (2001) Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc Natl Acad Sci USA 98:12491–12496PubMedCrossRefGoogle Scholar
  94. Kruh GD, Belinsky MG, Gallo JM et al (2007) Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice. Cancer Metastasis Rev 26:5–14PubMedCrossRefGoogle Scholar
  95. Kwong RW, Niyogi S (2009) The interactions of iron with other divalent metals in the intestinal tract of a freshwater teleost, rainbow trout (Oncorhynchusmykiss). Comp Biochem Physiol C Toxicol Pharmacol 150:442–449PubMedCrossRefGoogle Scholar
  96. L’hoste S, Chargui A, Belfodil R et al (2009) CFTR mediates cadmium-induced apoptosis through modulation of ROS level in mouse proximal tubule cells. Free Radic Biol Med 46:1017–1031PubMedCrossRefGoogle Scholar
  97. L’Hoste S, Chargui A, Belfodil R et al (2010) CFTR mediates apoptotic volume decrease and cell death by controlling glutathione efflux and ROS production in cultured mice proximal tubules. Am J Physiol Renal Physiol 298:F435–F453PubMedCrossRefGoogle Scholar
  98. Lacinova L, Klugbauer N, Hofmann F (2000) Regulation of the calcium channel alpha(1G) subunit by divalent cations and organic blockers. Neuropharmacology 39:1254–1266PubMedCrossRefGoogle Scholar
  99. Lane TW, Morel FM (2000) A biological function for cadmium in marine diatoms. Proc Natl Acad Sci USA 97:4627–4631PubMedCrossRefGoogle Scholar
  100. Lansman JB, Hess P, Tsien RW (1986) Blockade of current through single calcium channels by Cd2+, Mg2+, and Ca2+. Voltage and concentration dependence of calcium entry into the pore. J Gen Physiol 88:321–347PubMedCrossRefGoogle Scholar
  101. Leazer TM, Liu Y, Klaassen CD (2002) Cadmium absorption and its relationship to divalent metal transporter-1 in the pregnant rat. Toxicol Appl Pharmacol 185:18–24PubMedCrossRefGoogle Scholar
  102. Leclerc M, Brunette MG, Couchourel D (2004) Aldosterone enhances renal calcium reabsorption by two types of channels. Kidney Int 66:242–250PubMedCrossRefGoogle Scholar
  103. Lee WK, Thévenod F (2006) A role for mitochondrial aquaporins in cellular life-and-death decisions? Am J Physiol Cell Physiol 291:C195–C202PubMedCrossRefGoogle Scholar
  104. Lee PL, Gelbart T, West C et al (1998) The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis 24:199–215PubMedCrossRefGoogle Scholar
  105. Lee WK, Bork U, Gholamrezaei F et al (2005a) Cd2+-induced cytochrome c release in apoptotic proximal tubule cells: role of mitochondrial permeability transition pore and Ca2+ uniporter. Am J Physiol Renal Physiol 288:F27–F39PubMedCrossRefGoogle Scholar
  106. Lee WK, Spielmann M, Bork U et al (2005b) Cd2+-induced swelling-contraction dynamics in isolated kidney cortex mitochondria: role of Ca2+ uniporter, K+ cycling, and protonmotive force. Am J Physiol Cell Physiol 289:C656–C664PubMedCrossRefGoogle Scholar
  107. Leslie EM, Liu J, Klaassen CD et al (2006) Acquired cadmium resistance in metallothionein-I/II(-/-) knockout cells: role of the T-type calcium channel Cacnalpha1G in cadmium uptake. Mol Pharmacol 69:629–639PubMedCrossRefGoogle Scholar
  108. Levesque M, Martineau C, Jumarie C et al (2008) Characterization of cadmium uptake and cytotoxicity in human osteoblast-like MG-63 cells. Toxicol Appl Pharmacol 231:308–317PubMedCrossRefGoogle Scholar
  109. Li ZS, Lu YP, Zhen RG et al (1997) A new pathway for vacuolar cadmium sequestration in Saccharomyces cerevisiae: YCF1-catalyzed transport of bis(glutathionato)cadmium. Proc Natl Acad Sci USA 94:42–47PubMedCrossRefGoogle Scholar
  110. Limaye DA, Shaikh ZA (1999) Cytotoxicity of cadmium and characteristics of its transport in cardiomyocytes. Toxicol Appl Pharmacol 154:59–66PubMedCrossRefGoogle Scholar
  111. Lipscombe D, Helton TD, Xu W (2004) L-type calcium channels: the low down. J Neurophysiol 92:2633–2641PubMedCrossRefGoogle Scholar
  112. Lis A, Barone TA, Paradkar PN et al (2004) Expression and localization of different forms of DMT1 in normal and tumor astroglial cells. Brain Res Mol Brain Res 122:62–70PubMedCrossRefGoogle Scholar
  113. Liu Z, Li H, Soleimani M et al (2008) Cd2+ versus Zn2+ uptake by the ZIP8 HCO3 -dependent symporter: kinetics, electrogenicity and trafficking. Biochem Biophys Res Commun 365:814–820PubMedCrossRefGoogle Scholar
  114. Lopin KV, Gray IP, Obejero-Paz CA et al (2007) Fe2+ block and permeation in α1G (CaV3.1) T-type calcium channels. Biophys J Biophys Soc Meet Abstr. 601a, Abstract, 2867-PosGoogle Scholar
  115. Mackenzie B, Hediger MA (2004) SLC11 family of H+-coupled metal-ion transporters NRAMP1 and DMT1. Pflugers Arch 447:571–579PubMedCrossRefGoogle Scholar
  116. Mackenzie B, Ujwal ML, Chang MH et al (2006) Divalent metal-ion transporter DMT1 mediates both H+-coupled Fe2+ transport and uncoupled fluxes. Pflugers Arch 451:544–558PubMedCrossRefGoogle Scholar
  117. Mackenzie B, Takanaga H, Hubert N et al (2007) Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1). Biochem J 403:59–69PubMedCrossRefGoogle Scholar
  118. Maranda B, Brown D, Bourgoin S et al (2001) Intra-endosomal pH-sensitive recruitment of the Arf-nucleotide exchange factor ARNO and Arf6 from cytoplasm to proximal tubule endosomes. J Biol Chem 276:18540–18550PubMedCrossRefGoogle Scholar
  119. Marcus Y (1985) Ion solvation. Wiley, New York, NYGoogle Scholar
  120. McKie AT, Marciani P, Rolfs A et al (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5:299–309PubMedCrossRefGoogle Scholar
  121. Miethke M, Marahiel MA (2007) Siderophore-based iron acquisition and pathogen control. Microbiol Mol Biol Rev 71:413–451PubMedCrossRefGoogle Scholar
  122. Misra UK, Gawdi G, Akabani G et al (2002) Cadmium-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms. Cell Signal 14:327–340PubMedCrossRefGoogle Scholar
  123. Monteilh-Zoller MK, Hermosura MC, Nadler MJ et al (2003) TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions. J Gen Physiol 121:49–60PubMedCrossRefGoogle Scholar
  124. Mori K, Lee HT, Rapoport D et al (2005) Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 115:610–621PubMedGoogle Scholar
  125. Murakami T, Ohmori H, Katoh T et al (1991) Cadmium causes increases of N-myc and multidrug-resistance gene mRNA in neuroblastoma cells. J UOEH 13:271–278PubMedGoogle Scholar
  126. Nawrot T, Plusquin M, Hogervorst J et al (2006) Environmental exposure to cadmium and risk of cancer: a prospective population-based study. Lancet Oncol 7:119–126PubMedCrossRefGoogle Scholar
  127. Nawrot TS, Van Hecke E, Thijs L et al (2008) Cadmium-related mortality and long-term secular trends in the cadmium body burden of an environmentally exposed population. Environ Health Perspect 116:1620–1628PubMedCrossRefGoogle Scholar
  128. Neilands JB (1981) Microbial iron compounds. Annu Rev Biochem 50:715–731PubMedCrossRefGoogle Scholar
  129. Nieboer E, Richardson DHS (1980) The replacement of the nondescript term “heavy metals” by a biologically and chemically significant classification of metal ions. Environ Pollut Ser B 1:3–26CrossRefGoogle Scholar
  130. Nordberg GF (2009) Historical perspectives on cadmium toxicology. Toxicol Appl Pharmacol 238:192–200PubMedCrossRefGoogle Scholar
  131. O’Donnell EK, Sedlacek RL, Singh AK et al (2000) Inhibition of enterotoxin-induced porcine colonic secretion by diarylsulfonylureas in vitro. Am J Physiol Gastrointest Liver Physiol 279:G1104–G1112PubMedGoogle Scholar
  132. Obejero-Paz CA, Gray IP, Jones SW (2008) Ni2+ block of CaV3.1 (alpha1G) T-type calcium channels. J Gen Physiol 132:239–250PubMedCrossRefGoogle Scholar
  133. Ohno Y, Birn H, Christensen EI (2005) In vivo confocal laser scanning microscopy and micropuncture in intact rat. Nephron Exp Nephrol 99:17–25CrossRefGoogle Scholar
  134. Okubo M, Yamada K, Hosoyamada M et al (2003) Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes. Toxicol Appl Pharmacol 187:162–167PubMedCrossRefGoogle Scholar
  135. Olivi L, Bressler J (2000) Maitotoxin stimulates Cd influx in Madin-Darby kidney cells by activating Ca-permeable cation channels. Cell Calcium 27:187–193PubMedCrossRefGoogle Scholar
  136. Olivi L, Sisk J, Bressler J (2001) Involvement of DMT1 in uptake of Cd in MDCK cells: role of protein kinase C. Am J Physiol Cell Physiol 281:C793–C800PubMedGoogle Scholar
  137. Orlando RA, Rader K, Authier F et al (1998) Megalin is an endocytic receptor for insulin. J Am Soc Nephrol 9:1759–1766PubMedGoogle Scholar
  138. Parekh AB, Penner R (1997) Store depletion and calcium influx. Physiol Rev 77:901–930PubMedGoogle Scholar
  139. Park JD, Cherrington NJ, Klaassen CD (2002) Intestinal absorption of cadmium is associated with divalent metal transporter 1 in rats. Toxicol Sci 68:288–294PubMedCrossRefGoogle Scholar
  140. Pastan I, Gottesman MM, Ueda K et al (1988) A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc Natl Acad Sci USA 85:4486–4490PubMedCrossRefGoogle Scholar
  141. Penner R, Fleig A (2007) The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. Handb Exp Pharmacol 179:313–328PubMedCrossRefGoogle Scholar
  142. Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83:117–161PubMedGoogle Scholar
  143. Pesch B, Haerting J, Ranft U et al (2000) Occupational risk factors for renal cell carcinoma: agent-specific results from a case-control study in Germany. MURC Study Group. Multicenter urothelial and renal cancer study. Int J Epidemiol 29:1014–1024PubMedCrossRefGoogle Scholar
  144. Playford RJ, Belo A, Poulsom R et al (2006) Effects of mouse and human lipocalin homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair. Gastroenterology 131:809–817PubMedCrossRefGoogle Scholar
  145. Potier M, Trebak M (2008) New developments in the signaling mechanisms of the store-operated calcium entry pathway. Pflugers Arch 457:405–415PubMedCrossRefGoogle Scholar
  146. Prakriya M, Feske S, Gwack Y et al (2006) Orai1 is an essential pore subunit of the CRAC channel. Nature 443:230–233PubMedCrossRefGoogle Scholar
  147. Prozialeck WC, Grunwald GB, Dey PM et al (2002) Cadherins and NCAM as potential targets in metal toxicity. Toxicol Appl Pharmacol 182:255–265PubMedCrossRefGoogle Scholar
  148. Raja KB, Jafri SE, Peters TJ et al (2006) Iron and cadmium uptake by duodenum of hypotransferrinaemic mice. Biometals 19:547–553PubMedCrossRefGoogle Scholar
  149. Riccardi D, Hall AE, Chattopadhyay N et al (1998) Localization of the extracellular Ca2+/polyvalent cation-sensing protein in rat kidney. Am J Physiol 274:F611–F622PubMedGoogle Scholar
  150. Riordan JR (2008) CFTR function and prospects for therapy. Annu Rev Biochem 77:701–726PubMedCrossRefGoogle Scholar
  151. Sabirov RZ, Okada Y (2005) ATP release via anion channels. Purinergic Signal 1:311–328PubMedCrossRefGoogle Scholar
  152. Satarug S, Moore MR (2004) Adverse health effects of chronic exposure to low-level cadmium in foodstuffs and cigarette smoke. Environ Health Perspect 112:1099–1103PubMedCrossRefGoogle Scholar
  153. Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV et al (2007) Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res 67:9609–9612PubMedCrossRefGoogle Scholar
  154. Shafer TJ (2000) The role of ion channels in the transport of metals into excitable and nonexcitable cells. In: Zalups RK, Koropatnick J (eds) Molecular biology and toxicology of metals. Taylor & Francis, London, pp 179–207Google Scholar
  155. Silverman JA (1999) Multidrug-resistance transporters. Pharm Biotechnol 12:353–386PubMedCrossRefGoogle Scholar
  156. Smith CP, Thévenod F (2009) Iron transport and the kidney. Biochim Biophys Acta 1790:724–730PubMedGoogle Scholar
  157. Smith JB, Dwyer SD, Smith L (1989) Cadmium evokes inositol polyphosphate formation and calcium mobilization. Evidence for a cell surface receptor that cadmium stimulates and zinc antagonizes. J Biol Chem 264:7115–7118PubMedGoogle Scholar
  158. Souza V, Bucio L, Gutierrez-Ruiz MC (1997) Cadmium uptake by a human hepatic cell line (WRL-68 cells). Toxicology 120:215–220PubMedCrossRefGoogle Scholar
  159. Su MA, Trenor CC, Fleming JC et al (1998) The G185R mutation disrupts function of the iron transporter Nramp2. Blood 92:2157–2163PubMedGoogle Scholar
  160. Swandulla D, Armstrong CM (1989) Calcium channel block by cadmium in chicken sensory neurons. Proc Natl Acad Sci USA 86:1736–1740PubMedCrossRefGoogle Scholar
  161. Tabuchi M, Yoshimori T, Yamaguchi K et al (2000) Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells. J Biol Chem 275:22220–22228PubMedCrossRefGoogle Scholar
  162. Tabuchi M, Tanaka N, Nishida-Kitayama J et al (2002) Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms. Mol Biol Cell 13:4371–4387PubMedCrossRefGoogle Scholar
  163. Talavera K, Nilius B (2006) Biophysics and structure-function relationship of T-type Ca2+ channels. Cell Calcium 40:97–114PubMedCrossRefGoogle Scholar
  164. Thévenod F (2003) Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol 93:87–93CrossRefGoogle Scholar
  165. Thévenod F (2009) Cadmium and cellular signaling cascades: to be or not to be? Toxicol Appl Pharmacol 238:221–239PubMedCrossRefGoogle Scholar
  166. Thévenod F, Jones SW (1992) Cadmium block of calcium current in frog sympathetic neurons. Biophys J 63:162–168PubMedCrossRefGoogle Scholar
  167. Thévenod F, Friedmann JM, Katsen AD et al (2000) Up-regulation of multidrug resistance P-glycoprotein via nuclear factor-kappaB activation protects kidney proximal tubule cells from cadmium- and reactive oxygen species-induced apoptosis. J Biol Chem 275:1887–1896PubMedCrossRefGoogle Scholar
  168. Thévenod F, Wolff NA, Bork U et al (2007) Cadmium induces nuclear translocation of beta-catenin and increases expression of c-myc and Abcb1a in kidney proximal tubule cells. Biometals 20:807–820PubMedCrossRefGoogle Scholar
  169. Tommasini R, Evers R, Vogt E et al (1996) The human multidrug resistance-associated protein functionally complements the yeast cadmium resistance factor 1. Proc Natl Acad Sci USA 93:6743–6748PubMedCrossRefGoogle Scholar
  170. van de Graaf SF, Bindels RJ, Hoenderop JG (2007) Physiology of epithelial Ca2+ and Mg2+ transport. Rev Physiol Biochem Pharmacol 158:77–160PubMedCrossRefGoogle Scholar
  171. Verma JN, Wassef NM, Wirtz RA et al (1991) Phagocytosis of liposomes by macrophages: intracellular fate of liposomal malaria antigen. Biochim Biophys Acta 1066:229–238PubMedCrossRefGoogle Scholar
  172. Verroust PJ, Birn H, Nielsen R et al (2002) The tandem endocytic receptors megalin and cubilin are important proteins in renal pathology. Kidney Int 62:745–756PubMedCrossRefGoogle Scholar
  173. Vig M, Peinelt C, Beck A et al (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–1223PubMedCrossRefGoogle Scholar
  174. Waalkes MP (2003) Cadmium carcinogenesis. Mutat Res 533:107–120PubMedGoogle Scholar
  175. Waisberg M, Joseph P, Hale B et al (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 192:95–117PubMedCrossRefGoogle Scholar
  176. Wang X, Ghio AJ, Yang F et al (2002) Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 282:L987–L995PubMedGoogle Scholar
  177. Wang X, Bompadre SG, Li M et al (2009) Mutations at the signature sequence of CFTR create a Cd(2+)-gated chloride channel. J Gen Physiol 133:69–77PubMedCrossRefGoogle Scholar
  178. Ward DT, McLarnon SJ, Riccardi D (2002) Aminoglycosides increase intracellular calcium levels and ERK activity in proximal tubular OK cells expressing the extracellular calcium-sensing receptor. J Am Soc Nephrol 13:1481–1489PubMedCrossRefGoogle Scholar
  179. Wedeen RP, De Broe ME (1998) Heavy metals and the kidney. In: Davison AM (ed) Oxford textbook of clinical nephrology. Oxford University Press, Oxford, UK, pp 1175–1189Google Scholar
  180. Wolff NA, Abouhamed M, Verroust PJ et al (2006) Megalin-dependent internalization of cadmium-metallothionein and cytotoxicity in cultured renal proximal tubule cells. J Pharmacol Exp Ther 318:782–791PubMedCrossRefGoogle Scholar
  181. Wolff NA, Lee WK, Abouhamed M et al (2008) Role of ARF6 in internalization of metal-binding proteins, metallothionein and transferrin, and cadmium-metallothionein toxicity in kidney proximal tubule cells. Toxicol Appl Pharmacol 230:78–85PubMedCrossRefGoogle Scholar
  182. Yeromin AV, Zhang SL, Jiang W et al (2006) Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443:226–229PubMedCrossRefGoogle Scholar
  183. Yu AS, Hebert SC, Lee SL et al (1992) Identification and localization of renal Na(+)-Ca2+ exchanger by polymerase chain reaction. Am J Physiol 263:F680–F685PubMedGoogle Scholar
  184. Zasloff M (2007) Antimicrobial peptides, innate immunity, and the normally sterile urinary tract. J Am Soc Nephrol 18:2810–2816PubMedCrossRefGoogle Scholar
  185. Zhang SL, Yeromin AV, Zhang XH et al (2006) Genome-wide RNAi screen of Ca(2+) influx identifies genes that regulate Ca(2+) release-activated Ca(2+) channel activity. Proc Natl Acad Sci USA 103:9357–9362PubMedCrossRefGoogle Scholar
  186. Zimmerhackl LB, Momm F, Wiegele G et al (1998) Cadmium is more toxic to LLC-PK1 cells than to MDCK cells acting on the cadherin-catenin complex. Am J Physiol 275:F143–F153PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  1. 1.Department of Physiology and PathophysiologyUniversity of Witten/HerdeckeWittenGermany

Personalised recommendations