Abstract
Cadmium (Cd2+) is a toxic and non-essential divalent metal ion in eukaryotic cells. Cells can only be targeted by Cd2+ if it hijacks physiological high-affinity entry pathways, which transport essential divalent metal ions in a process termed “ionic and molecular mimicry”. Hence, “free” Cd2+ ions and Cd2+ complexed with small organic molecules are transported across cellular membranes via ion channels, carriers and ATP hydrolyzing pumps, whereas receptor-mediated endocytosis (RME) internalizes Cd2+-protein complexes. Only Cd2+ transport pathways validated by stringent methodology, namely electrophysiology, 109Cd2+ tracer studies, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd2+-sensitive fluorescent dyes, or specific ligand binding and internalization assays for RME are reviewed whereas indirect correlative studies are excluded. At toxicologically relevant concentrations in the submicromolar range, Cd2+ permeates voltage-dependent Ca2+ channels (“T-type” CaV3.1, CatSper), transient receptor potential (TRP) channels (TRPA1, TRPV5/6, TRPML1), solute carriers (SLCs) (DMT1/SLC11A2, ZIP8/SLC39A8, ZIP14/SLC39A14), amino acid/cystine transporters (SLC7A9/SLC3A1, SLC7A9/SLC7A13), and Cd2+-protein complexes are endocytosed by the lipocalin-2/NGAL receptor SLC22A17. Cd2+ transport via the mitochondrial Ca2+ uniporter, ATPases ABCC1/2/5 and transferrin receptor 1 is likely but requires further evidence. Cd2+ flux occurs through the influx carrier OCT2/SLC22A2, efflux MATE proteins SLC47A1/A2, the efflux ATPase ABCB1, and RME of Cd2+-metallothionein by the receptor megalin (low density lipoprotein receptor-related protein 2, LRP2):cubilin albeit at high concentrations thus questioning their relevance in Cd2+ loading. Which Cd2+-protein complexes are internalized by megalin:cubilin in vivo still needs to be determined. A stringent conservative and reductionist approach is mandatory to verify relevance of transport pathways for Cd2+ toxicity and to overcome dissemination of unsubstantiated conjectures.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abergel RJ, Clifton MC, Pizarro JC, Warner JA, Shuh DK, Strong RK, Raymond KN (2008) The siderocalin/enterobactin interaction: a link between mammalian immunity and bacterial iron transport. J Am Chem Soc 130:11524–11534. https://doi.org/10.1021/ja803524w
Abouhamed M 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–F1533. https://doi.org/10.1152/ajprenal.00359.2005
Abouhamed M, Wolff NA, Lee WK, Smith CP, Thévenod F (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–F712. https://doi.org/10.1152/ajprenal.00198.2007
Adiele RC, Stevens D, Kamunde C (2010) Reciprocal enhancement of uptake and toxicity of cadmium and calcium in rainbow trout (Oncorhynchus mykiss) liver mitochondria. Aquat Toxicol 96:319–327. https://doi.org/10.1016/j.aquatox.2009.11.019
Adiele RC, Stevens D, Kamunde C (2012) Features of cadmium and calcium uptake and toxicity in rainbow trout (Oncorhynchus mykiss) mitochondria. Toxicol In Vitro 26:164–173. https://doi.org/10.1016/j.tiv.2011.10.017
Akintola DF, Sampson B, Fleck A (1995) Development of an enzyme-linked immunosorbent assay for human metallothionein-1 in plasma and urine. J Lab Clin Med 126:119–127
Ballatori N, Krance SM, Marchan R, Hammond CL (2009) Plasma membrane glutathione transporters and their roles in cell physiology and pathophysiology. Mol Aspects Med 30:13–28. https://doi.org/10.1016/j.mam.2008.08.004
Bao G et al (2010) Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat Chem Biol 6:602–609. https://doi.org/10.1038/nchembio.402
Barbier O, Jacquillet G, Tauc M, Poujeol P, Cougnon M (2004) Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo. Am J Physiol Renal Physiol 287:F1067–F1075. https://doi.org/10.1152/ajprenal.00120.2004
Bennett KM, Liu J, Hoelting C, Stoll J (2011) Expression and analysis of two novel rat organic cation transporter homologs, SLC22A17 and SLC22A23. Mol Cell Biochem 352:143–154. https://doi.org/10.1007/s11010-011-0748-y
Beyer EC, Berthoud VM (2017) Gap junction structure: unraveled, but not fully revealed. F1000 Res 6:568. https://doi.org/10.12688/f1000research.10490.1
Beyersmann D, Hechtenberg S (1997) Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol Appl Pharmacol 144:247–261. https://doi.org/10.1006/taap.1997.8125
Bolignano D, Donato V, Lacquaniti A, Fazio MR, Bono C, Coppolino G, Buemi M (2010) Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: a new protein enters the scene. Cancer Lett 288:10–16. https://doi.org/10.1016/j.canlet.2009.05.027
Borregaard N, Cowland JB (2006) Neutrophil gelatinase-associated lipocalin, a siderophore-binding eukaryotic protein. Biometals 19:211–215. https://doi.org/10.1007/s10534-005-3251-7
Bouron A, Kiselyov K, Oberwinkler J (2015) Permeation, regulation and control of expression of TRP channels by trace metal ions. Pflugers Arch 467:1143–1164. https://doi.org/10.1007/s00424-014-1590-3
Bressler JP, Olivi L, Cheong JH, Kim Y, Bannona D (2004) Divalent metal transporter 1 in lead and cadmium transport. Ann N Y Acad Sci 1012:142–152
Bruggeman IM, Temmink JH, van Bladeren PJ (1992) Effect of glutathione and cysteine on apical and basolateral uptake and toxicity of CdCl(2) in kidney cells (LLC-PK(1)). Toxicol In Vitro 6:195–200
Bystrom LM, Guzman ML, Rivella S (2014) Iron and reactive oxygen species: friends or foes of cancer cells? Antioxid Redox Signal 20:1917–1924. https://doi.org/10.1089/ars.2012.5014
Cai X, Clapham DE (2008) Evolutionary genomics reveals lineage-specific gene loss and rapid evolution of a sperm-specific ion channel complex: CatSpers and CatSperbeta. PLoS ONE 3:e3569. https://doi.org/10.1371/journal.pone.0003569
Canonne-Hergaux F, Gros P (2002) Expression of the iron transporter DMT1 in kidney from normal and anemic mk mice. Kidney Int 62:147–156
Carriere P, Mantha M, Champagne-Paradis S, Jumarie C (2011) Characterization of basolateral-to-apical transepithelial transport of cadmium in intestinal TC7 cell monolayers. Biometals 24:857–874. https://doi.org/10.1007/s10534-011-9440-7
Cataldi M, Perez-Reyes E, Tsien RW (2002) Differences in apparent pore sizes of low and high voltage-activated Ca2+ channels. J Biol Chem 277:45969–45976. https://doi.org/10.1074/jbc.M203922200
Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16:521–555. https://doi.org/10.1146/annurev.cellbio.16.1.521
Cens T, Rousset M, Kajava A, Charnet P (2007) Molecular determinant for specific Ca/Ba selectivity profiles of low and high threshold Ca2+ channels. J Gen Physiol 130:415–425. https://doi.org/10.1085/jgp.200709771
Chasteen DN (1977) Human serotransferrin: structure and function. Coord Chem Rev 22:1–36
Christensen EI, Birn H (2002) Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 3:256–266. https://doi.org/10.1038/nrm778
Christensen EI, Birn H, Storm T, Weyer K, Nielsen R (2012) Endocytic receptors in the renal proximal tubule. Physiology (Bethesda) 27:223–236. https://doi.org/10.1152/physiol.00022.2012
Ciarimboli G et al (2010) Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol 176:1169–1180. https://doi.org/10.2353/ajpath.2010.090610
Clarkson TW (1993) Molecular and ionic mimicry of toxic metals. Annu Rev Pharmacol Toxicol 33:545–571
Coffey R, Ganz T (2017) Iron homeostasis: an anthropocentric perspective. J Biol Chem 292:12727–12734. https://doi.org/10.1074/jbc.R117.781823
Cole SP (2014) Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future. Annu Rev Pharmacol Toxicol 54:95–117. https://doi.org/10.1146/annurev-pharmtox-011613-135959
Cornelis R et al (1996) Sample collection guidelines for trace elements in blood and urine. IUPAC Commission of Toxicology. J Trace Elem Med Biol 10:103–127
De Smet H, Blust R, Moens L (2001) Cadmium-binding to transferrin in the plasma of the common carp Cyprinus carpio. Comp Biochem Physiol C: Toxicol Pharmacol 128:45–53
Dean M, Allikmets R (2001) Complete characterization of the human ABC gene family. J Bioenerg Biomembr 33:475–479
Deshpande CN et al (2018) Calcium is an essential cofactor for metal efflux by the ferroportin transporter family. Nat Commun 9:3075. https://doi.org/10.1038/s41467-018-05446-4
Devireddy LR, Teodoro JG, Richard FA, Green MR (2001) Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science 293:829–834. https://doi.org/10.1126/science.1061075
Devireddy LR, Gazin C, Zhu X, Green MR (2005) A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123:1293–1305
Devireddy LR, Hart DO, Goetz DH, Green MR (2010) A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141:1006–1017. https://doi.org/10.1016/j.cell.2010.04.040
Di Paola S, Scotto-Rosato A, Medina DL (2018) TRPML1: the Ca((2 +))retaker of the lysosome. Cell Calcium 69:112–121. https://doi.org/10.1016/j.ceca.2017.06.006
Dickson LE, Wagner MC, Sandoval RM, Molitoris BA (2014) The proximal tubule and albuminuria: really! J Am Soc Nephrol 25:443–453. https://doi.org/10.1681/ASN.2013090950
Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H (2008) The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455:992–996. https://doi.org/10.1038/nature07311
Dong XP, Wang X, Xu H (2010) TRP channels of intracellular membranes. J Neurochem 113:313–328. https://doi.org/10.1111/j.1471-4159.2010.06626.x
Donovan A et al (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781. https://doi.org/10.1038/35001596
Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1:191–200
Dorta DJ et al (2003) A proposed sequence of events for cadmium-induced mitochondrial impairment. J Inorg Biochem 97:251–257
Drakesmith H, Nemeth E, Ganz T (2015) Ironing out ferroportin. Cell Metab 22:777–787. https://doi.org/10.1016/j.cmet.2015.09.006
Dudev T, Lim C (2012) Why voltage-gated Ca2+ and bacterial Na+ channels with the same EEEE motif in their selectivity filters confer opposite metal selectivity. Phys Chem Chem Phys 14:12451–12456. https://doi.org/10.1039/c2cp00036a
Eakin CM, Knight JD, Morgan CJ, Gelfand MA, Miranker AD (2002) Formation of a copper specific binding site in non-native states of beta-2-microglobulin. Biochemistry 41:10646–10656
Elinder CG, Friberg L, Lind B, Jawaid M (1983) Lead and cadmium levels in blood samples from the general population of Sweden. Environ Res 30:233–253
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–C1376
Fiori MC, Reuss L, Cuello LG, Altenberg GA (2014) Functional analysis and regulation of purified connexin hemichannels Frontiers in physiology 5:71. https://doi.org/10.3389/fphys.2014.00071
Flower DR (1996) The lipocalin protein family: structure and function. Biochem J 318(Pt 1):1–14
Fotiadis D, Kanai Y, Palacin M (2013) The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med 34:139–158. https://doi.org/10.1016/j.mam.2012.10.007
Frazer DM, Anderson GJ (2014) The regulation of iron transport. BioFactors 40:206–214. https://doi.org/10.1002/biof.1148
Freisinger E, Vasak M (2013) Cadmium in metallothioneins. Met Ions Life Sci 11:339–371. https://doi.org/10.1007/978-94-007-5179-8_11
Fujishiro H, Kubota K, Inoue D, Inoue A, Yanagiya T, Enomoto S, Himeno S (2011) Cross-resistance of cadmium-resistant cells to manganese is associated with reduced accumulation of both cadmium and manganese. Toxicology 280:118–125. https://doi.org/10.1016/j.tox.2010.12.002
Gadsby DC, Vergani P, Csanady L (2006) The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440:477–483. https://doi.org/10.1038/nature04712
Galaske RG, Van Liew JB, Feld LG (1979) Filtration and reabsorption of endogenous low-molecular-weight protein in the rat kidney. Kidney Int 16:394–403
Garrett SH, Sens MA, Todd JH, Somji S, Sens DA (1999) Expression of MT-3 protein in the human kidney. Toxicol Lett 105:207–214
Garza-Lopez E, Chavez JC, Santana-Calvo C, Lopez-Gonzalez I, Nishigaki T (2016) Cd(2+) sensitivity and permeability of a low voltage-activated Ca(2+) channel with CatSper-like selectivity filter. Cell Calcium 60:41–50. https://doi.org/10.1016/j.ceca.2016.03.011
Girijashanker K et al (2008) Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Mol Pharmacol 73:1413–1423. https://doi.org/10.1124/mol.107.043588
Goumakos W, Laussac JP, Sarkar B (1991) Binding of cadmium(II) and zinc(II) to human and dog serum albumins: an equilibrium dialysis and 113Cd-NMR study. Biochem Cell Biol 69:809–820
Gunshin H et al (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388:482–488. https://doi.org/10.1038/41343
Harris WR, Madsen LJ (1988) Equilibrium studies on the binding of cadmium(II) to human serum transferrin. Biochemistry 27:284–288
He L, Girijashanker K, Dalton TP, Reed J, Li H, Soleimani M, Nebert DW (2006) ZIP8, member of the solute-carrier-39 (SLC39) metal-transporter family: characterization of transporter properties. Mol Pharmacol 70:171–180. https://doi.org/10.1124/mol.106.024521
Hirning LD, Fox AP, McCleskey EW, Olivera BM, Thayer SA, Miller RJ, Tsien RW (1988) Dominant role of N-type Ca2+ channels in evoked release of norepinephrine from sympathetic neurons. Science 239:57–61
Hoch E, Lin W, Chai J, Hershfinkel M, Fu D, Sekler I (2012) Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity. Proc Natl Acad Sci USA 109:7202–7207. https://doi.org/10.1073/pnas.1200362109
Hvidberg V, Jacobsen C, Strong RK, Cowland JB, Moestrup SK, Borregaard N (2005) The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett 579:773–777. https://doi.org/10.1016/j.febslet.2004.12.031
Illing AC, Shawki A, Cunningham CL, Mackenzie B (2012) Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1. J Biol Chem 287:30485–30496. https://doi.org/10.1074/jbc.M112.364208
Jarup L, Akesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238:201–208. https://doi.org/10.1016/j.taap.2009.04.020
Jenkitkasemwong S, Wang CY, Mackenzie B, Knutson MD (2012) Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25:643–655. https://doi.org/10.1007/s10534-012-9526-x
Jeong SH, Habeebu SS, Klaassen CD (2000) Cadmium decreases gap junctional intercellular communication in mouse liver. Toxicol Sci 57:156–166
Jorge-Nebert LF, Galvez-Peralta M, Landero Figueroa J, Somarathna M, Hojyo S, Fukada T, Nebert DW (2015) Comparing gene expression during cadmium uptake and distribution: untreated versus oral Cd-treated wild-type and ZIP14 knockout mice. Toxicol Sci 143:26–35. https://doi.org/10.1093/toxsci/kfu204
Kambe T, Tsuji T, Hashimoto A, Itsumura N (2015) The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol Rev 95:749–784. https://doi.org/10.1152/physrev.00035.2014
Kamer KJ, Mootha VK (2015) The molecular era of the mitochondrial calcium uniporter. Nat Rev Mol Cell Biol 16:545–553. https://doi.org/10.1038/nrm4039
Kimura O, Endo T, Hotta Y, Sakata M (2005) Effects of P-glycoprotein inhibitors on transepithelial transport of cadmium in cultured renal epithelial cells, LLC-PK1 and LLC-GA5-COL 150. Toxicology 208:123–132. https://doi.org/10.1016/j.tox.2004.11.015
Kippler M, Goessler W, Nermell B, Ekstrom EC, Lonnerdal B, El Arifeen S, Vahter M (2009) Factors influencing intestinal cadmium uptake in pregnant Bangladeshi women—a prospective cohort study. Environ Res 109:914–921. https://doi.org/10.1016/j.envres.2009.07.006
Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268:10425–10432
Kjeldsen L, Cowland JB, Borregaard N (2000) Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse. Biochim Biophys Acta 1482:272–283
Klassen RB et al (2004) Megalin mediates renal uptake of heavy metal metallothionein complexes. Am J Physiol Renal Physiol 287:F393–F403. https://doi.org/10.1152/ajprenal.00233.2003
Koepsell H (2013) The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med 34:413–435. https://doi.org/10.1016/j.mam.2012.10.010
Koepsell H, Schmitt BM, Gorboulev V (2003) Organic cation transporters. Rev Physiol Biochem Pharmacol 150:36–90
Kogan I et al (2003) CFTR directly mediates nucleotide-regulated glutathione flux. EMBO J 22:1981–1989. https://doi.org/10.1093/emboj/cdg194
Koike A, Sou J, Ohishi A, Nishida K, Nagasawa K (2017) Inhibitory effect of divalent metal cations on zinc uptake via mouse Zrt-/Irt-like protein 8 (ZIP8). Life Sci 173:80–85. https://doi.org/10.1016/j.lfs.2016.12.006
Kovacs G, Danko T, Bergeron MJ, Balazs B, Suzuki Y, Zsembery A, Hediger MA (2011) Heavy metal cations permeate the TRPV6 epithelial cation channel. Cell Calcium 49:43–55. https://doi.org/10.1016/j.ceca.2010.11.007
Kovacs G, Montalbetti N, Franz MC, Graeter S, Simonin A, Hediger MA (2013) Human TRPV5 and TRPV6: key players in cadmium and zinc toxicity. Cell Calcium 54:276–286. https://doi.org/10.1016/j.ceca.2013.07.003
Kruh GD, Belinsky MG (2003) The MRP family of drug efflux pumps. Oncogene 22:7537–7552. https://doi.org/10.1038/sj.onc.1206953
Lacinova L, Klugbauer N, Hofmann F (2000) Regulation of the calcium channel alpha(1G) subunit by divalent cations and organic blockers. Neuropharmacology 39:1254–1266
Langelueddecke C, Roussa E, Fenton RA, Wolff NA, Lee WK, Thévenod F (2012) Lipocalin-2 (24p3/neutrophil gelatinase-associated lipocalin (NGAL)) receptor is expressed in distal nephron and mediates protein endocytosis. J Biol Chem 287:159–169. https://doi.org/10.1074/jbc.M111.308296
Langelueddecke C, Roussa E, Fenton RA, Thévenod F (2013) Expression and function of the lipocalin-2 (24p3/NGAL) receptor in rodent and human intestinal epithelia. PLoS ONE 8:e71586. https://doi.org/10.1371/journal.pone.0071586
Langelueddecke C, Lee WK, Thévenod F (2014) Differential transcytosis and toxicity of the hNGAL receptor ligands cadmium-metallothionein and cadmium-phytochelatin in colon-like Caco-2 cells: implications for in vivo cadmium toxicity. Toxicol Lett 226:228–235. https://doi.org/10.1016/j.toxlet.2014.01.049
Lee WK, Bork U, Gholamrezaei F, Thévenod F (2005) Cd(2+)-induced cytochrome c release in apoptotic proximal tubule cells: role of mitochondrial permeability transition pore and Ca(2+) uniporter. Am J Physiol Renal Physiol 288:F27–F39. https://doi.org/10.1152/ajprenal.00224.2004
Lee WK, Torchalski B, Kohistani N, Thévenod F (2011) ABCB1 protects kidney proximal tubule cells against cadmium-induced apoptosis: roles of cadmium and ceramide transport. Toxicol Sci 121:343–356. https://doi.org/10.1093/toxsci/kfr071
Lee WK et al (2017) Initial autophagic protection switches to disruption of autophagic flux by lysosomal instability during cadmium stress accrual in renal NRK-52E cells. Arch Toxicol 91:3225–3245. https://doi.org/10.1007/s00204-017-1942-9
L’Hoste S et al (2009) CFTR mediates cadmium-induced apoptosis through modulation of ROS level in mouse proximal tubule cells. Free Radic Biol Med 46:1017–1031. https://doi.org/10.1016/j.freeradbiomed.2008.12.009
Li ZS, Lu YP, Zhen RG, Szczypka M, Thiele DJ, Rea PA (1997) A new pathway for vacuolar cadmium sequestration in Saccharomyces cerevisiae: YCF1-catalyzed transport of bis(glutathionato)cadmium. Proc Natl Acad Sci USA 94:42–47
Li M, Jiang J, Yue L (2006) Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7. J Gen Physiol 127:525–537. https://doi.org/10.1085/jgp.200609502
Liu J, Habeebu SS, Liu Y, Klaassen CD (1998a) Acute CdMT injection is not a good model to study chronic Cd nephropathy: comparison of chronic CdCl2 and CdMT exposure with acute CdMT injection in rats. Toxicol Appl Pharmacol 153:48–58. https://doi.org/10.1006/taap.1998.8506
Liu J, Liu Y, Habeebu SS, Klaassen CD (1998b) Susceptibility of MT-null mice to chronic CdCl2-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex. Toxicol Sci 46:197–203. https://doi.org/10.1006/toxs.1998.2541
Liu J, Goyer RA, Waalkes MP (2008a) Toxic effects of metals. In: Klaasen CD (ed) Casarett & Doull’s toxicology: the basic science of poisons, 7th edn. McGraw -Hill, New York, pp 931–979
Liu Z et al (2008b) Cd2+ versus Zn2+ uptake by the ZIP8 HCO3-dependent symporter: kinetics, electrogenicity and trafficking. Biochem Biophys Res Commun 365:814–820. https://doi.org/10.1016/j.bbrc.2007.11.067
Long Y, Li Q, Li J, Cui Z (2011a) Molecular analysis, developmental function and heavy metal-induced expression of ABCC5 in zebrafish. Comp Biochem Physiol B 158:46–55. https://doi.org/10.1016/j.cbpb.2010.09.005
Long Y, Li Q, Zhong S, Wang Y, Cui Z (2011b) Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals. Comp Biochem Physiol C 153:381–391. https://doi.org/10.1016/j.cbpc.2011.01.002
Lopin KV, Thévenod F, Page JC, Jones SW (2012) Cd(2)(+) block and permeation of CaV3.1 (alpha1G) T-type calcium channels: candidate mechanism for Cd(2)(+) influx. Mol Pharmacol 82:1183–1193. https://doi.org/10.1124/mol.112.080176
Madsen KM, Harris RH, Tisher CC (1982) Uptake and intracellular distribution of ferritin in the rat distal convoluted tubule. Kidney Int 21:354–361
Marcus Y (1988) Ionic radii in aqueous solutions Chem Rev 88:1475–1498
Maret W, Moulis JM (2013) The bioinorganic chemistry of cadmium in the context of its toxicity. Metal Ions Life Sci 11:1–29. https://doi.org/10.1007/978-94-007-5179-8_1
Martineau C, Abed E, Médina G, Jomphe LA, Mantha M, Jumarie C, Moreau R (2010) Involvement of transient receptor potential melastatin-related 7 (TRPM7) channels in cadmium uptake and cytotoxicity in MC3T3-E1 osteoblasts. Toxicol Lett 199(3):357–363
McAleer MA, Breen MA, White NL, Matthews N (1999) pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Biol Chem 274:23541–23548
Milnerowicz H, Bizon A (2010) Determination of metallothionein in biological fluids using enzyme-linked immunoassay with commercial antibody. Acta Biochim Pol 57:99–104
Mitchell CJ, Shawki A, Ganz T, Nemeth E, Mackenzie B (2014) Functional properties of human ferroportin, a cellular iron exporter reactive also with cobalt and zinc. Am J Physiol Cell Physiol 306:C450–C459. https://doi.org/10.1152/ajpcell.00348.2013
Miura S, Takahashi K, Imagawa T, Uchida K, Saito S, Tominaga M, Ohta T (2013) Involvement of TRPA1 activation in acute pain induced by cadmium in mice. Mol Pain 9:7. https://doi.org/10.1186/1744-8069-9-7
Montell C (2005) The TRP superfamily of cation channels. Sci STKE. https://doi.org/10.1126/stke.2722005re3
Mulier M, Vriens J, Voets T (2017) TRP channel pores and local calcium signals. Cell Calcium 66:19–24. https://doi.org/10.1016/j.ceca.2017.04.007
Nagamine T et al (2007) Analysis of tissue cadmium distribution in chronic cadmium-exposed mice using in-air micro-PIXE. Biol Trace Elem Res 117:115–126. https://doi.org/10.1007/BF02698088
Nagamori S et al (2016) Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1. Proc Natl Acad Sci USA 113:775–780. https://doi.org/10.1073/pnas.1519959113
Nemeth E et al (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093. https://doi.org/10.1126/science.1104742
Nemmiche S, Guiraud P (2016) Cadmium-induced oxidative damages in the human BJAB cells correlate with changes in intracellular trace elements levels and zinc transporters expression. Toxicol In Vitro 37:169–177. https://doi.org/10.1016/j.tiv.2016.09.014
Nies AT, Damme K, Kruck S, Schaeffeler E, Schwab M (2016) Structure and function of multidrug and toxin extrusion proteins (MATEs) and their relevance to drug therapy and personalized medicine. Arch Toxicol 90:1555–1584. https://doi.org/10.1007/s00204-016-1728-5
Nunez MT, Tapia V, Rojas A, Aguirre P, Gomez F, Nualart F (2010) Iron supply determines apical/basolateral membrane distribution of intestinal iron transporters DMT1 and ferroportin 1. Am J Physiol Cell Physiol 298:C477–C485. https://doi.org/10.1152/ajpcell.00168.2009
Ohrvik H, Tyden E, Artursson P, Oskarsson A, Tallkvist J (2013) Cadmium transport in a model of neonatal intestinal cells correlates to MRP1 and not DMT1 or FPN1. ISRN Toxicol 2013:892364. https://doi.org/10.1155/2013/892364
Okazaki Y, Ma Y, Yeh M, Yin H, Li Z, Yeh KY, Glass J (2012) DMT1 (IRE) expression in intestinal and erythroid cells is regulated by peripheral benzodiazepine receptor-associated protein 7. Am J Physiol Gastrointest Liver Physiol 302:G1180–G1190. https://doi.org/10.1152/ajpgi.00545.2010
Okubo M, Yamada K, Hosoyamada M, Shibasaki T, Endou H (2003) Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes. Toxicol Appl Pharmacol 187:162–167
Paragas N et al (2011) The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat Med 17:216–222. https://doi.org/10.1038/nm.2290
Parajuli LK, Nakajima C, Kulik A, Matsui K, Schneider T, Shigemoto R, Fukazawa Y (2012) Quantitative regional and ultrastructural localization of the Ca(v)2.3 subunit of R-type calcium channel in mouse brain. J Neurosci 32:13555–13567. https://doi.org/10.1523/JNEUROSCI.1142-12.2012
Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83:117–161. https://doi.org/10.1152/physrev.00018.2002
Prakriya M, Lewis RS (2015) Store-operated calcium channels. Physiol Rev 95:1383–1436. https://doi.org/10.1152/physrev.00020.2014
Prozialeck WC et al (2016) Evaluation of cystatin C as an early biomarker of cadmium nephrotoxicity in the rat. Biometals 29:131–146. https://doi.org/10.1007/s10534-015-9903-3
Richardson DR (2005) 24p3 and its receptor: dawn of a new iron age? Cell 123:1175–1177
Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566–578. https://doi.org/10.1038/nrm3412
Rozanski GM, Nath AR, Adams ME, Stanley EF (2013) Low voltage-activated calcium channels gate transmitter release at the dorsal root ganglion sandwich synapse. J Physiol 591:5575–5583. https://doi.org/10.1113/jphysiol.2013.260281
Sabolic I, Ljubojevic M, Herak-Kramberger CM, Brown D (2002) Cd-MT causes endocytosis of brush-border transporters in rat renal proximal tubules. Am J Physiol Renal Physiol 283:F1389–F1402
Sabolic I, Breljak D, Skarica M, Herak-Kramberger CM (2010) Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 23:897–926. https://doi.org/10.1007/s10534-010-9351-z
Saddala MS, Kandimalla R, Adi PJ, Bhashyam SS, Asupatri UR (2017) Novel 1, 4-dihydropyridines for L-type calcium channel as antagonists for cadmium toxicity. Sci Rep 7:45211. https://doi.org/10.1038/srep45211
Salmela SS, Vuori E, Huunan-Seppala A, Kilpio JO, Sumuvuori H (1983) Body burden of cadmium in man at low level of exposure. Sci Tot Environ 27:89–95
Santoyo-Sanchez MP, Pedraza-Chaverri J, Molina-Jijon E, Arreola-Mendoza L, Rodriguez-Munoz R, Barbier OC (2013) Impaired endocytosis in proximal tubule from subchronic exposure to cadmium involves angiotensin II type 1 and cubilin receptors. BMC Nephrol 14:211. https://doi.org/10.1186/1471-2369-14-211
Sather WA, McCleskey EW (2003) Permeation and selectivity in calcium channels. Annu Rev Physiol 65:133–159. https://doi.org/10.1146/annurev.physiol.65.092101.142345
Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, Barasch J (2007) Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 18:407–413
Sharom FJ (2011) The P-glycoprotein multidrug transporter. Essays Biochem 50:161–178. https://doi.org/10.1042/bse0500161
Shawki A, Knight PB, Maliken BD, Niespodzany EJ, Mackenzie B (2012) H(+)-coupled divalent metal-ion transporter-1: functional properties, physiological roles and therapeutics. Curr Topics Membr 70:169–214. https://doi.org/10.1016/B978-0-12-394316-3.00005-3
Shuba YM (2014) Models of calcium permeation through T-type channels. Pflugers Arch 466:635–644. https://doi.org/10.1007/s00424-013-1437-3
Smith CP, Thévenod F (2009) Iron transport and the kidney. Biochim Biophys Acta 1790:724–730. https://doi.org/10.1016/j.bbagen.2008.10.010
Soodvilai S, Nantavishit J, Muanprasat C, Chatsudthipong V (2011) Renal organic cation transporters mediated cadmium-induced nephrotoxicity. Toxicol Lett 204:38–42. https://doi.org/10.1016/j.toxlet.2011.04.005
Srigiridhar K, Nair KM (1998) Iron-deficient intestine is more susceptible to peroxidative damage during iron supplementation in rats. Free Radic Biol Med 25:660–665
Thévenod F (2003) Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol 93:p87–p93. https://doi.org/10.1159/000070241
Thévenod F (2010) Catch me if you can! Novel aspects of cadmium transport in mammalian cells. Biometals 23:857–875. https://doi.org/10.1007/s10534-010-9309-1
Thévenod F (2018) Membrane transport proteins and receptors for cadmium and cadmium complexes. In: Thévenod F, Petering D, Templeton D, Lee W-K, Hartwig A (eds) Cadmium interaction with animal cells. Springer, Cham, pp 1–22
Thévenod F, Jones SW (1992) Cadmium block of calcium current in frog sympathetic neurons. Biophys J 63:162–168. https://doi.org/10.1016/S0006-3495(92)81575-8
Thévenod F, Lee WK (2013a) Cadmium and cellular signaling cascades: interactions between cell death and survival pathways. Arch Toxicol 87:1743–1786. https://doi.org/10.1007/s00204-013-1110-9
Thévenod F, Lee WK (2013b) Toxicology of cadmium and its damage to Mammalian organs. Metal Ions Life Sci 11:415–490. https://doi.org/10.1007/978-94-007-5179-8_14
Thévenod F, Wolff NA (2016) Iron transport in the kidney: implications for physiology and cadmium nephrotoxicity. Metallomics 8:17–42. https://doi.org/10.1039/c5mt00215j
Thévenod F, Friedmann JM, Katsen AD, Hauser IA (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 275:1887–1896
Thévenod F et al (2013) Substrate- and cell contact-dependent inhibitor affinity of human organic cation transporter 2: studies with two classical organic cation substrates and the novel substrate Cd2+. Mol Pharm 10:3045–3056. https://doi.org/10.1021/mp400113d
Thijssen S, Maringwa J, Faes C, Lambrichts I, Van Kerkhove E (2007) Chronic exposure of mice to environmentally relevant, low doses of cadmium leads to early renal damage, not predicted by blood or urine cadmium levels. Toxicology 229:145–156
Tian J, Hu J, Chen M, Yin H, Miao P, Bai P, Yin J (2017) The use of mrp1-deficient (Danio rerio) zebrafish embryos to investigate the role of Mrp1 in the toxicity of cadmium chloride and benzo[a]pyrene. Aquat Toxicol 186:123–133. https://doi.org/10.1016/j.aquatox.2017.03.004
Tommasini R et al (1996) The human multidrug resistance-associated protein functionally complements the yeast cadmium resistance factor 1. Proc Natl Acad Sci USA 93:6743–6748
Torra M, To-Figueras J, Brunet M, Rodamilans M, Corbella J (1994) Total and metallothionein-bound cadmium in the liver and the kidney of a population in Barcelona (Spain). Bull Environ Contam Toxicol 53:509–515
Usai C, Barberis A, Moccagatta L, Marchetti C (1999) Pathways of cadmium influx in mammalian neurons. J Neurochem 72:2154–2161
Valiunas V, Cohen IS, Brink PR (2018) Defining the factors that affect solute permeation of gap junction channels Biochimica et biophysica acta. Biomembranes 1860:96–101. https://doi.org/10.1016/j.bbamem.2017.07.002
van de Graaf SF, Hoenderop JG, Bindels RJ (2006) Regulation of TRPV5 and TRPV6 by associated proteins. Am J Physiol Renal Physiol 290:F1295–F1302. https://doi.org/10.1152/ajprenal.00443.2005
van Goor MKC, Hoenderop JGJ, van der Wijst J (2017) TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6. Biochim Biophys Acta 1864:883–893. https://doi.org/10.1016/j.bbamcr.2016.11.027
van Raaij S et al (2018) Tubular iron deposition and iron handling proteins in human healthy kidney and chronic kidney disease Scientific reports 8:9353. https://doi.org/10.1038/s41598-018-27107-8
Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417. https://doi.org/10.1146/annurev.biochem.75.103004.142819
Vinken M, Ceelen L, Vanhaecke T, Rogiers V (2010) Inhibition of gap junctional intercellular communication by toxic metals. Chem Res Toxicol 23:1862–1867. https://doi.org/10.1021/tx100276f
Voets T, Talavera K, Owsianik G, Nilius B (2005) Sensing with TRP channels Nat Chem Biol 1:85–92. https://doi.org/10.1038/nchembio0705-85
Wang Y, Fang J, Leonard SS, Rao KM (2004) Cadmium inhibits the electron transfer chain and induces reactive oxygen species. Free Radic Biol Med 36:1434–1443. https://doi.org/10.1016/j.freeradbiomed.2004.03.010
Wang B et al (2007) Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line. Am J Physiol Cell Physiol 292:C1523–C1535. https://doi.org/10.1152/ajpcell.00409.2006
Wang L, Chen D, Wang H, Liu Z (2009) Effects of lead and/or cadmium on the expression of metallothionein in the kidney of rats. Biol Trace Elem Res 129:190–199. https://doi.org/10.1007/s12011-008-8288-3
Wang Y, Zalups RK, Barfuss DW (2010) Potential mechanisms involved in the absorptive transport of cadmium in isolated perfused rabbit renal proximal tubules. Toxicol Lett 193:61–68. https://doi.org/10.1016/j.toxlet.2009.12.007
Wang CY, Jenkitkasemwong S, Duarte S, Sparkman BK, Shawki A, Mackenzie B, Knutson MD (2012) ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J Biol Chem 287:34032–34043. https://doi.org/10.1074/jbc.M112.367284
Wang J, Wang J, Song W, Yang X, Zong W, Liu R (2016) Molecular mechanism investigation of the neutralization of cadmium toxicity by transferrin. Phys Chem Chem Phys 18:3536–3544. https://doi.org/10.1039/c5cp06100h
Wang X et al (2018) Physiological functions of ferroportin in the regulation of renal iron recycling and ischemic acute kidney injury. Am J Physiol Renal Physiol 315:F1042–F1057. https://doi.org/10.1152/ajprenal.00072.2018
Wennemuth G, Westenbroek RE, Xu T, Hille B, Babcock DF (2000) CaV2.2 and CaV2.3 (N- and R-type) Ca2+ channels in depolarization-evoked entry of Ca2+ into mouse sperm. J Biol Chem 275:21210–21217. https://doi.org/10.1074/jbc.M002068200
Wolff NA, Abouhamed M, Verroust PJ, Thévenod F (2006) Megalin-dependent internalization of cadmium-metallothionein and cytotoxicity in cultured renal proximal tubule cells. J Pharmacol Exp Ther 318:782–791. https://doi.org/10.1124/jpet.106.102574
Wolff NA, Liu W, Fenton RA, Lee WK, Thévenod F, Smith CP (2011) Ferroportin 1 is expressed basolaterally in rat kidney proximal tubule cells and iron excess increases its membrane trafficking. J Cell Mol Med 15:209–219. https://doi.org/10.1111/j.1582-4934.2009.00985.x
Wolff NA, Ghio AJ, Garrick LM, Garrick MD, Zhao L, Fenton RA, Thévenod F (2014) Evidence for mitochondrial localization of divalent metal transporter 1 (DMT1). FASEB J 28:2134–2145. https://doi.org/10.1096/fj.13-240564
Wolff NA, Garrick MD, Zhao L, Garrick LM, Ghio AJ, Thevenod F (2018) A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Sci Rep 8:211. https://doi.org/10.1038/s41598-017-18584-4
Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trends Cell Biol 26:165–176. https://doi.org/10.1016/j.tcb.2015.10.014
Yang XF, Yang YN (1997) Protective effects of calcium antagonists on cadmium-induced toxicity in rats Biomedical and environmental sciences: BES 10:402–407
Yang H, Guo D, Obianom ON, Su T, Polli JE, Shu Y (2017) Multidrug and toxin extrusion proteins mediate cellular transport of cadmium. Toxicol Appl Pharmacol 314:55–62. https://doi.org/10.1016/j.taap.2016.11.007
Yeung PS, Yamashita M, Prakriya M (2017) Pore opening mechanism of CRAC channels. Cell Calcium 63:14–19. https://doi.org/10.1016/j.ceca.2016.12.006
Yoshida M, Ohta H, Yamauchi Y, Seki Y, Sagi M, Yamazaki K, Sumi Y (1998) Age-dependent changes in metallothionein levels in liver and kidney of the Japanese. Biol Trace Elem Res 63:167–175
Yunker AM, McEnery MW (2003) Low-voltage-activated (“T-Type”) calcium channels in review. J Bioenerg Biomembr 35:533–575
Zalups RK, Ahmad S (2003) Molecular handling of cadmium in transporting epithelia. Toxicol Appl Pharmacol 186:163–188
Acknowledgements
Research in the laboratory was supported by the DFG, BMBF (01DN16039), the University of Witten/Herdecke and ZBAF. The authors thank Dr. Natascha A. Wolff (University of Witten/Herdecke) for valuable discussions.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Thévenod, F., Fels, J., Lee, WK. et al. Channels, transporters and receptors for cadmium and cadmium complexes in eukaryotic cells: myths and facts. Biometals 32, 469–489 (2019). https://doi.org/10.1007/s10534-019-00176-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10534-019-00176-6