Catch me if you can! Novel aspects of cadmium transport in mammalian cells

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.