Cloning and characterization of a mammalian proton-coupled metal-ion transporter

Abstract

Metal ions are essential cofactors for a wealth of biological processes, including oxidative phosphorylation, gene regulation and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary haemochromatosis, disorders of metal-ion deficiency, and certain neurodegenerative diseases. Despite their pivotal physiological roles, however, there is no molecular information on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+. DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential. It is a 561-amino-acid protein with 12 putative membrane-spanning domains and is ubiquitously expressed, most notably in the proximal duodenum. DCT1 is upregulated by dietary iron deficiency, and may represent a key mediator of intestinal iron absorption. DCT1 is a member of the 'natural-resistance-associated macrophage protein' (Nramp) family and thus its properties provide insight into how these proteins confer resistance to pathogens.

The role of lysosomes in iron metabolism and recycling

“…The Tf-TfR1 complex is re-circulated to the cell surface, where the neutral pH causes the iron-free Tf to dissociate from the receptor and be returned to the circulation (Gunshin et al, 1997, Ponka et al, 1998. Recently, a number of other iron-uptake mechanisms have been identified, especially for hepatocytes, which express transferrin receptor 2 (TfR2) that is a homolog to TfR1 (Graham et al, 2008, Kawabata et al, 2001, West et al, 2000.…”

Effects of Intracerebroventricular Injection of Iron Dextran on the Iron Concentration and Divalent Metal Transporter 1 Expression in the Caudate Putamen and Substantia Nigra of Rats

“…It was reported that DMT1 might have a role in Tf-dependent iron uptake in some types of cells (Wardrop and Richardson, 1999). In the brain, the existence of DMT1 and its functional characterization suggest that DMT1 might play an important physiological role in iron homeostasis in the brain (Gunshin et al, 1997;Andrews, 1999;Andrews et al, 1999;Burdo et al, 1999;Williams et al, 2000;Wang et al, 2001Wang et al, , 2002b. However, functional information is still lacking.…”

“…DMT1 has been shown to transport a variety of divalent metals including Fe 21 Harris et al, 1999;McKie et al, 2001). There are at least two different splice forms of DMT1: DMT1 (1IRE) mRNA containing iron-responsive element (IRE) in the 3 0 -UTR and DMT1 (2IRE) mRNA not containing a classical IRE (Gunshin et al, 1997;Lee et al, 1998).…”

“…Evidences showed that abundant DMT1 mRNA expresses in the striatum, substantia nigra, and other brain regions (Gunshin et al, 1997;Burdo et al, 2004;Knutson et al, 2004;Ke et al, 2005). An accumulation of iron occurs with age, and levels of DMT1 are correlated with iron staining in the monkey basal ganglia (Huang et al, 2004).…”

Importance of zinc in the elderly: the ZENITH study

“…In addition, the findings from metabolic studies and supplementation trials (Solomons, 1986;O'Brien et al, 2000) suggest an antagonist relationship between iron (Fe) and Zn, whereby Zn reduces the absorption of Fe and vice versa. Historically, the antagonism reported in literature was attributed to a competition between iron and zinc for transport by divalent metal transporter-1 (DMT1), which presents an affinity for iron and other divalent metals (Gunshin et al, 1997). But, recent studies show that Zn does not reduce Fe absorption, by virtue of the fact that the DMT1 is not implicated in the intestinal Zn absorption (Bannon et al, 2003).…”