Catch me if you can! Novel aspects of cadmium transport in mammalian cells
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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.
KeywordsCalcium 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.
- 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
- 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
- Hille B (1992) Ionic channels of excitable membranes. Sinauer Associates Inc, Sunderland, MAGoogle Scholar
- 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
- 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
- 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
- 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
- Marcus Y (1985) Ion solvation. Wiley, New York, NYGoogle Scholar
- 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
- 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