Disease relevance of SLC11A2

• Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload [1].
• The mechanism by which cirrhosis mediates this change in DMT1 expression has yet to be determined [2].
• There was no correlation between the duodenal expression of DMT1 and Ireg1 and the degree of hepatic siderosis [2].
• In cirrhosis, the expression of DMT1 and Ireg1 was not related to the severity of liver disease or cirrhosis type [2].
• RESULTS: Perl's staining showed increased iron in colorectal cancers, and there was a corresponding overexpression of components of the intracellular iron import machinery (DCYTB, DMT1, and TfR1) [3].
• We investigated the effects of hypoxia and hypoxia/re-oxygenation on the expression of DMT1 and the content of HIF-1alpha in HepG2 cells [4].

Psychiatry related information on SLC11A2

• Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease [5].

High impact information on SLC11A2

• Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMTi [6].
• DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential [7].
• As selective iron chelation prevents NMDA neurotoxicity in cortical cultures, the NMDA-NO-Dexras1-PAP7-DMT1-iron uptake signaling cascade also appears to mediate NMDA neurotoxicity [8].
• CONCLUSIONS: DMT1 and FP1 are centrally involved in iron uptake/transfer in the duodenum and in the adaptive changes of iron homeostasis to iron deficiency and overload [1].
• INTERPRETATION: Increased NRAMP-2 mRNA expression in duodenal mucosa of patients with hereditary haemochromatosis may promote duodenal iron uptake and lead to iron overload [9].

Chemical compound and disease context of SLC11A2

• Since plasma membrane expression of DMT1 is upregulated in liver of hemochromatosis patients, this H(+) -uncoupled facilitative Fe(2+) transport via DMT1 can account for the uptake of nontransferrin-bound plasma iron characteristic of iron overload disorders [10].
• Influence of parenteral iron preparations on non-transferrin bound iron uptake, the iron regulatory protein and the expression of ferritin and the divalent metal transporter DMT-1 in HepG2 human hepatoma cells [11].
• Cadmium toxicity could depend partly on the activity of Nramp2, and partly on metallothionein content [12].

Biological context of SLC11A2

• This may be mediated by an up regulation of the recently identified mucosal transporter DMT1 (Nramp2 or DCT1) for divalent cations [13].
• With iron feeding, DMT1 undergoes endocytosis and FPN translocates from the apical cytosol to the basolateral membrane [14].
• Analysis of cDNA derived by direct amplification of reversed transcribed RNA or cDNA clones isolated from a library provide evidence of skipping of exons 10 and 12 of nramp2 [15].
• The 5' regulatory region of nramp2 also contains five potential metal response elements (MRE's) that are similar to the MRE's found in the metallothionein-IIA gene, three potential SP1 binding sites and a single gamma-interferon regulatory element [15].
• The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms [15].

Anatomical context of SLC11A2

• Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells [16].
• Iron treatment downregulates DMT1 and IREG1 mRNA expression in Caco-2 cells [17].
• The aim of this study was to investigate the effects of iron treatment on DMT1 and IREG1 mRNA expression in Caco-2 cells, a human intestinal cell line [17].
• This interaction may be critical in small-intestinal crypt cells which express HFE, where it may function to modulate their intrinsic iron status thereby programming iron absorption by DMT-1 in the mature enterocyte [18].
• In undifferentiated Caco-2 cells, DMT-1 localized to a discrete late endosome compartment distinct from that occupied by HFE where, in addition to brush-border iron uptake, it may function to regulate the availability of iron delivery to intracellular iron pools [18].

Associations of SLC11A2 with chemical compounds

• These results indicated that NRAMP2 is localized to the late endosomes and lysosomes, where NRAMP2 may function to transfer the endosomal free Fe(2+) into the cytoplasm in the transferrin cycle [16].
• Ferrous iron uptake is facilitated by DMT-1 (Nramp-2, DCT-1) in a pathway shared with manganese [19].
• One of these, 1303C-->A, occurs in the coding region of nramp2 and results in an amino acid change from leucine to isolecine [15].
• Our data further indicates upregulation of DMT-1 and IREG-1 mRNA and protein in response to high levels of glucose [20].
• Nuclear run-off analysis then demonstrated that the effects of iron and desferrioxamine on DMT1 and FPN1 mRNA expression are rather due to modulation of transcription of these genes [21].

Physical interactions of SLC11A2

• Iron is released from transferrin as the result of the acidic pH in endosome and then is transported to the cytosol by DMT1 [22].
• The membrane topology and transport properties of Nramp1HA and Nramp2HA were indistinguishable, suggesting that Nramp1 divalent-metal transport at the phagosomal membrane is mechanistically similar to that of Nramp2 at the membrane of acidified endosomes [23].

Co-localisations of SLC11A2

• Interestingly, neither form of DMT1 colocalizes with the transferrin receptor [24].

Regulatory relationships of SLC11A2

• BACKGROUND AND AIMS: While upregulation of divalent metal transporter 1 (DMT1) and iron regulated gene 1 (IREG1) within duodenal enterocytes is reported in patients with hereditary haemochromatosis (HH), these findings are controversial [25].
• The Nramp1 protein is expressed at the phagosomal membrane of macrophages and neutrophils and is a paralog of the Nramp2 (Slc11a2) iron transporter [23].

Other interactions of SLC11A2

• To characterize better the potential mechanisms for iron transport into and within the brain, we have analyzed expression patterns of two factors: divalent metal transporter 1 (DMT1) and stimulator of Fe transport (SFT) [26].
• Identification of the molecular interactions of HFE with DMT-1 and other key components of the iron transport pathway has implications for a mechanistic understanding of the pathophysiology of human iron storage diseases as well as the regulation of normal iron balance [18].
• Our data show that expression levels of human DCT1 mRNA, and to a lesser extent IREG1 mRNA, are regulated in an iron-dependent manner, whereas mRNA of hephaestin is not affected [27].
• In controls, we found inverse relationships between the DCT1 splice form containing an iron-responsive element (IRE) and blood hemoglobin, serum transferrin saturation, or ferritin [27].
• The additional exons and introns account for much of the difference in length between nramp2 (> 36 kb) and nramp1 (12 kb) [15].

Analytical, diagnostic and therapeutic context of SLC11A2

• METHODS: DMT1, FP1 messenger RNA (mRNA), and protein expression were analyzed in duodenal biopsy specimens from patients by means of TaqMan real-time polymerase chain reaction, Western blotting technique, and immunohistochemistry [1].
• The intracellular localization of endogenous NRAMP2 and recombinant green fluorescent protein (GFP)-NRAMP2 was examined by immunofluorescence staining and by native fluorescence of GFP, respectively [16].
• DMT1 expression was significantly increased in HH patients who had undergone phlebotomy therapy (treated) and in patients with ID compared with controls [25].
• DMT-1 protein expression was additionally assessed by immunohistochemistry [28].
• DESIGN: A case-control study design was used to compare the frequencies of five polymorphisms in SLC11A1 and three in SLC11A2 between a group of bacteriologically confirmed TB patients and healthy community controls [29].

References