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PMID:17293870

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Citation

Ludwiczek, S, Theurl, I, Muckenthaler, MU, Jakab, M, Mair, SM, Theurl, M, Kiss, J, Paulmichl, M, Hentze, MW, Ritter, M and Weiss, G (2007) Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat. Med. 13:448-54

Abstract

Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues, leading to eventual organ failure. We have discovered a new mechanism to reverse iron overload-pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Its additional functions in iron handling in the kidney and liver are less well understood. We show that the L-type calcium channel blocker nifedipine increases DMT-1-mediated cellular iron transport 10- to 100-fold at concentrations between 1 and 100 microM. Mechanistically, nifedipine causes this effect by prolonging the iron-transporting activity of DMT-1. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium channel blockers emerges as a new pharmacological therapy for the treatment of iron overload disorders.

Links

PubMed Online version:10.1038/nm1542

Keywords

Animals; Biological Transport, Active/drug effects; COS Cells; Calcium Channel Blockers/pharmacology; Calcium Channel Blockers/therapeutic use; Cation Transport Proteins/metabolism; Cercopithecus aethiops; Electrophysiology; Hemochromatosis/prevention & control; Humans; Immunoblotting; Iron/metabolism; Iron/urine; Iron Overload/drug therapy; Liver/metabolism; Mice; Mice, Knockout; Microarray Analysis; Nifedipine/pharmacology; Nifedipine/therapeutic use; Reverse Transcriptase Polymerase Chain Reaction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NRAM2

involved_in

GO:0034755: iron ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRAM2

GO:0005384: manganese ion transmembrane transporter activity

ECO:0000314:

F

complete

HUMAN:NRAM2

GO:0006828: manganese ion transport

ECO:0000314:

P

P

complete

HUMAN:NRAM2

GO:0015093: ferrous iron transmembrane transporter activity

ECO:0000314:

F

complete

HUMAN:NRAM2

enables

GO:0005384: manganese ion transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NRAM2

involved_in

GO:0006828: manganese ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRAM2

enables

GO:0015093: ferrous iron transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NRAM2

involved_in

GO:0006826: iron ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NRAM2

involved_in

GO:0034755: iron ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q8IUD7

involved_in

GO:0034755: iron ion transmembrane transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q8IUD7

involved_in

GO:0006826: iron ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q8IUD7

enables

GO:0015093: ferrous iron transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:Q8IUD7

involved_in

GO:0006828: manganese ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:Q8IUD7

enables

GO:0005384: manganese ion transmembrane transporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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