Membrane Transport Proteins and Receptors for Cadmium and Cadmium Complexes

  • Frank ThévenodEmail author


Cadmium (Cd2+) is a non-essential divalent metal ion without physiological function in animal cells. For toxicity to occur, Cd2+ must first enter cells by utilizing physiological transport pathways for essential divalent metal ions, such as Fe2+, Zn2+, Cu2+, Ca2+, or Mn2+. ‘Free’ Cd2+ ions and Cd2+ ions bound to small organic molecules are transported via ion channels, carrier proteins or ATP hydrolyzing pumps, whereas metalloproteins are internalized by receptor-mediated endocytosis (RME). This review describes Cd2+ transport (influx/efflux) pathways that were validated by electrophysiology (e.g. patch clamp), 109Cd2+ flux, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd2+-sensitive fluorescent dyes, specific ligand binding, and ligand internalization assays that are ideally studied in heterologous expression systems. Convincing evidence has been obtained for Cd2+ permeation for Ca2+ channels at toxicologically relevant concentrations (CaV3.1, CatSper) TRP channels (TRPA1, TRPV5/6, TRPML1), solute carriers (DMT1, ZIP8, ZIP14, system (b0, + AT)) and RME of Cd2+-protein complexes (Lipocalin-2 receptor). The carrier OCT2 mediates Cd2+ influx and MATE1/2 and the ATPase ABCB1 Cd2+ efflux at high, toxicologically irrelevant Cd2+ concentrations. L- and N-type voltage-, ligand-gated, store-operated Ca2+ channels, CFTR, connexins and the transporter ferroportin-1 are not permeated by Cd2+. More experimental evidence is needed for the mitochondrial Ca2+ uniporter, the ATPase ABCC1 and the transferrin receptor 1. Although the receptor megalin: cubilin mediates RME of Cd2+-metallothionein complex at high, but toxicologically irrelevant concentrations, its in vivo Cd2+-protein–ligand complexes still need to be identified. A stringent methodology is mandatory to prove additional Cd2+ transport pathways instead of propagating unsubstantiated speculations.



Research is supported by a grant from BMBF (01DN16039), the University of Witten/Herdecke and ZBAF. The author thanks Dr. Wing-Kee Lee (University of Witten/Herdecke) for valuable discussions.


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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Physiology, Pathophysiology & Toxicology and Centre for Biomedical Education and Research (ZBAF), Faculty of HealthUniversity of Witten/HerdeckeWittenGermany

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