Department of Physiology and Pathophysiology, University of Witten/Herdecke, Stockumer Str. 12, Witten, Germany.
Biometals. 2010 Oct;23(5):857-75. doi: 10.1007/s10534-010-9309-1. Epub 2010 Mar 5.
Cadmium (Cd(2+)) is a nonessential divalent metal ion that causes toxicity in multiple organs in humans. In order for toxicity to occur Cd(2+) must first enter cells by utilizing transport pathways for essential metals. This review focuses on studies in which Cd(2+) transport was directly demonstrated by electrophysiological, radiotracer or Cd(2+)-sensitive fluorescent dye techniques. The chemistry of Cd(2+) 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 Cd(2+) has been demonstrated for the Fe(2+)/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 Cd(2+) 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 Cd(2+) by the multidrug resistance P-glycoprotein remains controversial. Finally, arguments for and against Cd(2+) transport by Ca(2+) channels are presented. Most N- and L-type Ca(2+) channels are closed at resting membrane potential (with the exception of CaV1.3 channels) and therefore unlikely to allow significant Cd(2+) influx under physiological conditions. CaV3.1 and CaV3.2 T-type calcium channels are permeated by divalent metal ions, such as Fe(2+) and Mn(2+) because of considerable "window" currents close to resting membrane potential and could be responsible for tonic Cd(2+) entry. TRPM7 and the mitochondrial Ca(2+) uniporter are other likely candidates for Cd(2+) transporters, whereas the role of Orai proteins, the store-operated calcium channels carrying Ca(2+) release-activated Ca(2+) current, in Cd(2+) influx remains to be investigated.
镉（Cd(2+)）是一种非必需的二价金属离子，会对人体多个器官造成毒性。为了产生毒性，Cd(2+) 必须首先通过利用必需金属的转运途径进入细胞。本综述重点介绍了通过电生理学、放射性示踪剂或 Cd(2+)敏感荧光染料技术直接证明 Cd(2+)转运的研究。Cd(2+) 和一般金属离子的化学性质在与通过膜蛋白转运相关的性质方面得到了阐述，例如水合能。除了 ZIP 转运体 SLC39A8 和 SLC39A14 的转运（本综述不涉及该内容）之外，已经证明游离 Cd(2+)可以通过 Fe(2+)/H(+)共转运体二价金属转运蛋白 1 摄取。此外，多配体内吞受体 megalin 和 cubilin 通过受体介导的内吞作用摄取镉-金属硫蛋白复合物。还讨论了 ATP 结合盒转运蛋白在细胞内 Cd(2+)外排中的作用。多药耐药相关蛋白 1 和囊性纤维化跨膜电导调节因子很可能将镉-谷胱甘肽复合物转运出细胞，而多药耐药 P-糖蛋白对游离 Cd(2+)的转运仍存在争议。最后，提出了 Cd(2+)通过钙通道转运的正反论据。大多数 N-型和 L-型钙通道在静息膜电位下关闭（除了 CaV1.3 通道），因此在生理条件下不太可能允许大量 Cd(2+)内流。CaV3.1 和 CaV3.2 T-型钙通道可被二价金属离子（如 Fe(2+)和 Mn(2+)）通透，因为在接近静息膜电位时有相当大的“窗口”电流，可能负责持续的 Cd(2+)内流。TRPM7 和线粒体钙单向转运体是其他可能的 Cd(2+)转运体候选物，而 Orai 蛋白（携带 Ca(2+)释放激活的 Ca(2+)电流的储存操作钙通道）在 Cd(2+)内流中的作用仍有待研究。
