Cadmium (Cd) is a toxic and non-essential divalent metal ion in eukaryotic cells. Cells can only be targeted by Cd if it hijacks physiological high-affinity entry pathways, which transport essential divalent metal ions in a process termed "ionic and molecular mimicry". Hence, "free" Cd ions and Cd complexed with small organic molecules are transported across cellular membranes via ion channels, carriers and ATP hydrolyzing pumps, whereas receptor-mediated endocytosis (RME) internalizes Cd-protein complexes. Only Cd transport pathways validated by stringent methodology, namely electrophysiology, Cd tracer studies, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd-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, Cd permeates voltage-dependent Ca channels ("T-type" Ca3.1, 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 Cd-protein complexes are endocytosed by the lipocalin-2/NGAL receptor SLC22A17. Cd transport via the mitochondrial Ca uniporter, ATPases ABCC1/2/5 and transferrin receptor 1 is likely but requires further evidence. Cd flux occurs through the influx carrier OCT2/SLC22A2, efflux MATE proteins SLC47A1/A2, the efflux ATPase ABCB1, and RME of Cd-metallothionein by the receptor megalin (low density lipoprotein receptor-related protein 2, LRP2):cubilin albeit at high concentrations thus questioning their relevance in Cd loading. Which Cd-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 Cd toxicity and to overcome dissemination of unsubstantiated conjectures.
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