Channels, transporters and receptors for cadmium and cadmium complexes in eukaryotic cells: myths and facts

Frank Thévenod; Johannes Fels; Wing-Kee Lee; Ralf Zarbock

doi:10.1007/s10534-019-00176-6

Channels, transporters and receptors for cadmium and cadmium complexes in eukaryotic cells: myths and facts

Biometals. 2019 Jun;32(3):469-489. doi: 10.1007/s10534-019-00176-6. Epub 2019 Jan 30.

Authors

Frank Thévenod¹, Johannes Fels², Wing-Kee Lee², Ralf Zarbock²

Affiliations

¹ Department of Physiology, Pathophysiology & Toxicology and ZBAF (Centre for Biomedical Education and Research), Faculty of Health, School of Medicine, Witten/Herdecke University, Stockumer Str 12 (Thyssenhaus), 58453, Witten, Germany. frank.thevenod@uni-wh.de.
² Department of Physiology, Pathophysiology & Toxicology and ZBAF (Centre for Biomedical Education and Research), Faculty of Health, School of Medicine, Witten/Herdecke University, Stockumer Str 12 (Thyssenhaus), 58453, Witten, Germany.

PMID: 30701379
DOI: 10.1007/s10534-019-00176-6

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" Ca_V3.1, 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.

Keywords: ABC transporters; Ca2+ channels; Cadmium toxicity; Lipocalin-2 receptor; Megalin; Solute carriers.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport Systems / metabolism*
Cadmium / metabolism*
Cadmium / pharmacology
Cell Membrane / drug effects
Cell Membrane / metabolism
Coordination Complexes / metabolism*
Coordination Complexes / pharmacology
Eukaryotic Cells / drug effects
Eukaryotic Cells / metabolism*
Humans
Ion Channels / metabolism*
Receptors, Cell Surface / metabolism*

Substances

Amino Acid Transport Systems
Coordination Complexes
Ion Channels
Receptors, Cell Surface
Cadmium