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Cited by 218Iron Metabolism and DisordersTrace Elements in HealthDrug Transport and Resistance Mechanisms

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Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter

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GOSWAMI, Tapasree, BHATTACHARJEE, Arin, BABAL, Paul, SEARLE, Susan, MOORE, Elizabeth, LI, Ming, BLACKWELL, Jenefer M.·2001·Biochemical Journal
DOI 10.1042/bj3540511PMC PMC1221682
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Abstract

In mammals, natural-resistance-associated macrophage protein 1 (Nramp1) regulates macrophage activation and is associated with infectious and autoimmune diseases. Nramp2 is associated with anaemia. Both belong to a highly conserved eukaryote/prokaryote protein family. We used Xenopus oocytes to demonstrate that, like Nramp2, Nramp1 is a bivalent cation (Fe2+, Zn2+ and Mn2+) transporter. Strikingly, however, where Nramp2 is a symporter of H+ and metal ions, Nramp1 is a highly pH-dependent antiporter that fluxes metal ions in either direction against a proton gradient. At pH9.0, oocytes injected with cRNA from wild-type murine Nramp1 with a glycine residue at position 169 (Nramp1G169; P = 3.22×10-6) and human NRAMP1 (P = 3.87×10-5) showed significantly enhanced uptake of radiolabelled Zn2+ compared with water-injected controls. At pH5.5, Nramp1G169 (P = 1.34×10-13) and NRAMP1 (P = 1.09×10-6) oocytes showed significant efflux of Zn2+. Zn2+ transport was abolished when the proton gradient was dissipated using carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Using pre-acidified oocytes, currents of 130±57 nA were evoked by 100µM Zn2+ at pH7.5, and 139±47 nA by 100µM Fe2+ at pH7.0, in Nramp1G169 oocytes; currents of 254±49 nA and 242±26 nA were evoked, respectively, in NRAMP1 oocytes. Steady-state currents evoked by increasing concentrations of Zn2+ were saturable, with apparent affinity constants of approx. 614nM for Nramp1G169 and approx. 562nM for NRAMP1 oocytes, and a curvilinear voltage dependence of transporter activity (i.e. the data points approximate to a curve that approaches a linear asymptote). In the present study we propose a new model for metal ion homoeostasis in macrophages. Under normal physiological conditions, Nramp2, localized to early endosomal membranes, delivers extracellularly acquired bivalent cations into the cytosol. Nramp1, localized to late endosomal/lysosomal membranes, delivers bivalent cations from the cytosol into this acidic compartment where they may directly affect antimicrobial activity.

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  1. 50 Evans, C. A. W., Harbuz, M. S., Ostenfeld, T., Norrish, A. and Blackwell, J. M. (2001) Nramp1 is expressed in neurones and is associated with behavioural and immune responses to stress. Neurogenetics, in the press

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Metadata

Authors
GOSWAMI, T., BHATTACHARJEE, A., BABAL, P., SEARLE, S., MOORE, E., LI, M., & BLACKWELL, J. M.
Affiliations
  • Addenbrooke's Hospital (GB)
  • University of South Alabama (US)
Corresponding author
  • GOSWAMI, Tapasree
  • SEARLE, Susan
ORCID
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2001-03-08
Volume
354
Issue
3
Pages
511-519
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj3540511
PMC
PMC1221682
OpenAlex
W2016821205
Cited by
218
References
0
Citations by year
2026: 3 · 2025: 8 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 12 · 2017: 7 · 2016: 7 · 2015: 5 · 2014: 8 · 2013: 8 · 2012: 11
FWCI
9.02
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Wellcome Trust (065642)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
NRAMP1, DMT1, metal ion transport, zinc transport, iron transport, manganese transport, proton gradient, pH-dependent transport, macrophage activation, Xenopus oocyte expression
MeSH terms
Natural Resistance-associated Macrophage Protein 1, Animals, Carrier Proteins, Cations, Divalent, Electric Conductivity, Female, Hydrogen-Ion Concentration, Immunohistochemistry, Membrane Proteins, Microscopy, Electron, Models, Biological, Oocytes, Protons, Substrate Specificity, Xenopus, Mutagenesis, Site-Directed, Ion Pumps, Ion Transport, Cation Transport Proteins

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