DMT1: Which metals does it transport?

Abstract

DMT1-Divalent Metal (Ion) Transporter 1 or SLC11A2/DCT1/Nramp2-transports Fe 2+ into the duodenum and out of the endosome during the transferrin cycle. DMT1 also is important in non-transferrin bound iron uptake. It plays similar roles in Mn 2+ trafficking. Voltage clamping showed that six other metals evoked currents, but it is unclear if these metals are substrates for DMT1. This report summarizes progress on which metals DMT1 transports, focusing on results from the authors' labs. We recently cloned 1A/+IRE and 2/-IRE DMT1 isoforms to generate HEK293 cell lines that express them in a tetracycline-inducible fashion, then compared induced expression to uninduced expression and to endogenous DMT1 expression. Induced expression increases ~50x over endogenous expression and ~10x over uninduced levels. Fe 2+ , Mn 2+ , Ni 2+ and Cu 1+ or Cu 2+ are transported. We also explored competition between metal ions using this system because incorporation essentially represents DMT1 transport and find this order for transport affinity: Mn>?Cd>?Fe>Pb~Co~Ni>Zn. The effects of decreased DMT1 also could be examined. The Belgrade rat has diminished DMT1 function and thus provides ways of testing. A series of DNA constructs that generate siRNAs specific for DMT1 or certain DMT1 isoforms yield another way to test DMT1-based transport.

Ascorbate enhances iron uptake into intestinal cells through formation of a FeCl3–ascorbate complex

“…The uptake of FeCl 3 across the apical membrane of Caco-2 cells has been well-documented to be a protein-mediated process, with several proteins capable of playing the role of iron transporter (Garrick et al 2006). This observation was confirmed by the saturable, hyperbolic nature of 55 Fe(II) uptake (Fig.…”

Substrate Profile and Metal-ion Selectivity of Human Divalent Metal-ion Transporter-1

“…These observations add to previous findings of metal-ion transport in mammalian cell lines expressing DMT1 and in brushborder membrane vesicles isolated from the DMT1-deficient Belgrade rat (27, 28, 32, 33, 36 -39). The importance of also determining which metal ions are not DMT1 substrates has been stressed elsewhere (40), and this study considerably extends for DMT1 the catalog of nonsubstrates.…”

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

“…In turn, this iron exporter reduces intracellular iron otherwise available to pathogens. As a sequella of infection, release of the inflammatory cytokine IL-6 induces the expression of hepcidin, an iron regulatory hormone, which binds to ferroportin and promotes its internalization and degradation in lysosomes (56). This mechanism ultimately diminishes the release of iron from macrophages, which play an important role in recycling the metal from senescent red cells after erythrophagocytosis.…”