DMT1, a physiologically relevant apical Cu¹⁺transporter of intestinal cells

Abstract

Despite important advances in the understanding of copper secretion and excretion, the molecular components of intestinal copper absorption remain a mystery. DMT1, also known as Nramp2 and DCT1, is the transporter responsible for intestinal iron uptake. Electrophysiological evidence suggests that DMT1 can also be a copper transporter. Thus we examined the potential role of DMT1 as a copper transporter in intestinal Caco-2 cells. Treatment of cells with a DMT1 antisense oligonucleotide resulted in 80 and 48% inhibition of iron and copper uptake, respectively. Cells incorporated considerable amounts of copper as Cu1+, whereas Cu2+ transport was about 10-fold lower. Cu1+inhibited apical Fe2+ transport. Fe2+, but not Fe3+, effectively inhibited Cu1+ uptake. The iron content of the cells influenced both copper and iron uptake. Cells with low iron content transported fourfold more iron and threefold more copper than cells with high iron content. These results demonstrate that DMT1 is a physiologically relevant Cu1+ transporter in intestinal cells, indicating that intestinal absorption of copper and iron are intertwined.

Vesicular transport of Fe and interaction with other metal ions in polarized Caco2 Cell monolayers

“…Thus, DMT1 has binding sites for several metal ions and not only for divalent metal ions. This is consistent with the findings of Arredondo et al (2003), that Cu(I) transport by Caco2 cells is altered when DMT1 expression is manipulated through anti-sense technology. We have tended to think of DMT1 as being a large transmembrane protein with one or more channels that allows transfer of such metal ions.…”

“…The original studies of Gunshin et al (1997) suggested that many divalent metal ions might use this transporter, since they (like iron) produced an inward current. However, other studies showed that certain metals (like Zn) might not use DMT1 (Tallkvist et al, 2000), and those of Arredondo et al (2003) indicated Cu(I) rather than Cu(II) uptake by DMT1. Our own earlier studies and those of Arredondo et al (2003) with Caco2 cell monolayers showed that iron deficiency, which increases expression of DMT1, also enhances Cu uptake Zerounian et al, 2003) and that reduced expression of DMT1 (through anti-sense oligomer treatment) also reduced uptake of copper (Arredondo et al, 2003).…”

“…However, other studies showed that certain metals (like Zn) might not use DMT1 (Tallkvist et al, 2000), and those of Arredondo et al (2003) indicated Cu(I) rather than Cu(II) uptake by DMT1. Our own earlier studies and those of Arredondo et al (2003) with Caco2 cell monolayers showed that iron deficiency, which increases expression of DMT1, also enhances Cu uptake Zerounian et al, 2003) and that reduced expression of DMT1 (through anti-sense oligomer treatment) also reduced uptake of copper (Arredondo et al, 2003). In the studies described here, we took a kinetic approach, reasoning that if Cu and Mn ions compete for uptake with Fe(II), they could reduce initial rates of Fe(II) uptake and that competitive kinetics would be demonstrated.…”

The Role of Zinc, Manganse and Copper in Rumen Metabolism and Immune Function: A Review Article

“…An alternative explanation is provided by [95] who demonstrate that excess Fe can compete with Cu for its absorption at intestinal level, by saturating the DMT-1 Cu transporter.…”

Effect of calcium-fortified milk-rich diets (either goat’s or cow’s milk) on copper bioavailability in iron-deficient anemia

“…In a previous study, this effect had been shown in ID rats before supplying the diet with Fe (Rodríguez-Matas et al 1998). There have been some reports on isolated epithelial cells, suggesting that the main intestinal Fe transporter DMT1 (divalent metal ion transporter) can also transport Cu across the apical membrane (Arredondo et al 2003;Sharp 2004) and this transporter could be regulated by both Fe and Cu (Arredondo et al 2003). Extended periods of iron deficiency could lead to an up-regulation of DMT1 expression which subsequently produces an increase in Cu absorption in ID rats.…”