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

Cadmium (Cd ²⁺ ) is a toxic and non-essential divalent metal ion in eukaryotic cells. Cells can only be targeted by Cd ²⁺ 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 ²⁺ ions and Cd ²⁺ 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 ²⁺ -protein complexes. Only Cd ²⁺ transport pathways validated by stringent methodology, namely electrophysiology, ¹⁰⁹ Cd ²⁺ tracer studies, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd ²⁺ -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 ²⁺ permeates voltage-dependent Ca ²⁺ channels ("T-type" Ca _V 3.1, 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 ²⁺ -protein complexes are endocytosed by the lipocalin-2/NGAL receptor SLC22A17. Cd ²⁺ transport via the mitochondrial Ca ²⁺ uniporter, ATPases ABCC1/2/5 and transferrin receptor 1 is likely but requires further evidence. Cd ²⁺ flux occurs through the influx carrier OCT2/SLC22A2, efflux MATE proteins SLC47A1/A2, the efflux ATPase ABCB1, and RME of Cd ²⁺ -metallothionein by the receptor megalin (low density lipoprotein receptor-related protein 2, LRP2):cubilin albeit at high concentrations thus questioning their relevance in Cd ²⁺ loading. Which Cd ²⁺ -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 ²⁺ toxicity and to overcome dissemination of unsubstantiated conjectures.