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" CaV3.1, 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.

中文翻译：

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真核细胞中镉和镉复合物的通道，转运蛋白和受体：神话与事实。

镉（Cd2 +）是真核细胞中有毒且非必需的二价金属离子。如果Cd2 +劫持了生理学高亲和力的进入途径，则该细胞只能被Cd2 +靶向，该途径在称为“离子和分子模拟”的过程中运输必需的二价金属离子。因此，与小有机分子复合的“游离” Cd2 +离子和Cd2 +通过离子通道，载体和ATP水解泵跨细胞膜转运，而受体介导的内吞作用（RME）使Cd2 +-蛋白质复合物内在化。只有Cd2 +传输途径已通过严格的方法论验证，这些方法包括电生理学，109Cd2 +示踪剂研究，电感耦合等离子体质谱法，原子吸收光谱法，Cd2 +敏感的荧光染料，或对RME的特异性配体结合和内在化分析进行了综述，但不包括间接相关研究。在亚微摩尔范围内的毒理学相关浓度下，Cd2 +渗透电压依赖性Ca2 +通道（“ T型” CaV3.1，CatSper），瞬时受体电位（TRP）通道（TRPA1，TRPV5 / 6，TRPML1），溶质载体（SLC） ）（DMT1 / SLC11A2，ZIP8 / SLC39A8，ZIP14 / SLC39A14），氨基酸/胱氨酸转运蛋白（SLC7A9 / SLC3A1，SLC7A9 / SLC7A13）和Cd2 +蛋白复合物被lipocalin-2 / NGAL受体SLC22A17内吞。Cd2 +可能通过线粒体Ca2 +单向转运蛋白，ATPases ABCC1 / 2/5和转铁蛋白受体1转运，但需要进一步的证据。通过流入载体OCT2 / SLC22A2，外排MATE蛋白SLC47A1 / A2，外排ATPase ABCB1，受体巨蛋白（低密度脂蛋白受体相关蛋白2，LRP2）：胆红素对Cd2 +-金属硫蛋白的RME和RME的影响，尽管浓度很高，因此质疑了它们在Cd2 +负载中的相关性。megalin：cubilin在体内内化了哪些Cd2 +-蛋白复合物仍需要确定。必须采用严格的保守和还原主义方法来验证Cd2 +毒性运输途径的相关性，并克服未证实的猜想的传播。