Copper transport 1 (CTR1) plays a critical role in copper uptake by cells, but several studies demonstrated that divalent metal transporter 1 (DMT1) also transports copper in some cells and under certain circumstances. The present study was undertaken to determine the relationship between CTR1 and DMT1 in copper uptake. Human umbilical vein endothelial cells (HUVECs) were exposed to increasing concentrations of extracellular copper in cultures, leading to increased accumulation of copper in cells proportional to concentrations of extracellular copper. However, CTR1 proteins decreased in relation to the increase in copper concentrations, and DMT1 increased inversely correlating to the decrease in CTR1. Gene silencing of either CTR1 or DMT1 did not affect copper accumulation in cells, but deficiency in both CTR1 and DMT1 resulted in a complete inhibition of copper uptake. This study thus demonstrates that DMT1 imports copper under the condition of CTR1 deficiency, and vice versa. Therefore, CTR1 and DMT1 would compensate for each other for copper uptake in mammalian cells, although different types of cells may use either one as a predominant copper importer under physiological conditions.
