Zn2+ transporters and Zn2+ homeostasis in neurons

https://doi.org/10.1016/j.ejphar.2003.08.067Get rights and content

Abstract

Although the presence of Zn2+ in the brain has been known for nearly half a century, only recently has its precise location and potential roles as a neuromodulator and signaling molecule as well as neurotoxic agent come to the forefront. Unfortunately, our understanding of Zn2+ homeostatic mechanisms lags far behind. The recent identification of presumed Zn2+ transporters has opened new approaches to studying Zn2+ homeostatic mechanisms in neurons. Zn2+ transporters are involved in separate Zn2+ influx and efflux pathways in neurons. However, we are only beginning to understand the mechanism of Zn2+ transport and much more research needs to be done. We are only beginning to understand the transcriptional control and cellular location of Zn2+ transporters, as well. Finally, this review presents a working model of neuronal Zn2+ homeostasis and discusses the experimental evidence for the proposed roles that Zn2+ transporters might play.

Section snippets

The Zn2+-containing cell: unifying concepts in Zn2+ transport and homeostasis

This review will combine old and new research findings addressing Zn2+ biology, building a conceptual framework describing our understanding of Zn2+ homeostasis in the neuron and the role played by Zn2+ transporters. We will certainly focus on new and exciting findings, areas of controversy, and will try to highlight gaps in our knowledge. Our first task will describe briefly the role Zn2+ plays in the nervous system and why Zn2+ homeostasis is important. Zn2+ is an essential trace element

What are the resting intracellular and extracellular concentrations of free Zn2+ in the brain?

The amount of Zn2+ in the mammalian brain averages about 10 μg/g (wet weight) and is fairly uniform over different regions or when comparing the grey and white matter (Frederickson, 1989). Although interesting developmental changes in brain Zn2+ occur, little change in total brain Zn2+ is observed with aging (Frederickson, 1989). Presumably then, the total amount of Zn2+ in the extracellular fluid and cytosol is fairly constant throughout the brain. Zn2+ concentration in the serum and

Zinc transporters: several different zinc transporter families have been identified; each family probably has a unique transport mechanism, function, and cellular location

In eukaryotic organisms, three families of metal cation transporters have now been identified and well characterized and others are certainly yet to be discovered. Most studies of the identification and functional characterization of these transporters have not been done in neurons, but what we do know from functional studies and expression analysis in brain suggests that these transporters are present in neurons and function in ways similar to those better characterized in other eukaryotic

ZnT transporters

Whereas ZnT-1 has ubiquitous expression (including the brain), the other ZnT family members show tissue-specific expression. We know little about the factors that control the tissue-specific transcriptional regulation of ZnT family members. It appears that ZnT-1, -3, -4, -5, -6, and hZTL1 are expressed in the brain. The transcriptional regulation and the control of the cellular localization of the various ZnT transporters expressed in the brain are probably complex, but by analogy with simpler

Summary

A better understanding of neuronal Zn2+ homeostasis and Zn2+ transporters will be critical for defining not only the role(s) played by Zn2+ in cell signaling, but also the role Zn2+ plays in neurodegenerative human diseases. Much has been learned in the last 10 years, but much more is still to be discovered. Now is an exciting time to be involved in Zn2+ research. This review presents a working model of neuronal Zn2+ homeostasis, which is most notable for the number of question marks contained

References (114)

  • N. Franco-Pons et al.

    Zinc-rich synaptic boutons in human temporal cortex biopsies

    Neuroscience

    (2000)
  • C.J. Frederickson

    Neurobiology of zinc and zinc-containing neurons

    Int. Rev. Neurobiol.

    (1989)
  • C.J. Frederickson et al.

    Cytoarchitectonic distribution of zinc in the hippocampus of man and the rat

    Brain Res.

    (1983)
  • C.J. Frederickson et al.

    Loss of zinc staining from hippocampal mossy fibers during kainic acid induced seizures: a histofluorescence study

    Brain Res.

    (1988)
  • C.J. Frederickson et al.

    Translocation of zinc may contribute to seizure-induced death of neurons

    Brain Res.

    (1989)
  • C.J. Frederickson et al.

    Nitric oxide causes apparent release of zinc from presynaptic boutons

    Neuroscience

    (2002)
  • L.A. Gaither et al.

    Functional expression of the human hZIP2 zinc transporter

    J. Biol. Chem.

    (2000)
  • L.A. Gaither et al.

    The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells

    J. Biol. Chem.

    (2001)
  • H. Haase et al.

    Intracellular zinc distribution and transport in C6 rat glioma cells

    Biochem. Biophys. Res. Commun.

    (2002)
  • L. Huang et al.

    Functional characterization of a novel mammalian zinc transporter, ZnT6

    J. Biol. Chem.

    (2002)
  • D. Jiang et al.

    Zn(2+) induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria

    J. Biol. Chem.

    (2001)
  • S.M. Jo et al.

    Zinc-enriched (ZEN) terminals in mouse spinal cord: immunohistochemistry and autometallography

    Brain Res.

    (2000)
  • T. Kambe et al.

    Cloning and characterization of a novel mammalian zinc transporter, zinc transporter 5, abundantly expressed in pancreatic beta cells

    J. Biol. Chem.

    (2002)
  • S.L. Kelleher et al.

    Zinc transporters in the mammary gland respond to marginal zinc and vitamin A intake during lactation

    J. Nutr.

    (2002)
  • Y.H. Kim et al.

    The role of NADPH oxidase and neuronal nitric oxide synthase in zinc-induced poly(ADP-ribose) polymerase activation and cell death in cortical culture

    Exp. Neurol.

    (2002)
  • A.H. Kim et al.

    L-type Ca2+ channel-mediated Zn2+ toxicity and modulation by ZnT-1 in PC12 cells

    Brain Res.

    (2000)
  • C.P. Kirschke et al.

    ZnT7, a novel mammalian transporter, accumulates zinc in the golgi apparatus

    J. Biol. Chem.

    (2003)
  • I. Korichneva et al.

    Zinc release from protein kinase C as the common event during activation by lipid second messenger or reactive oxygen

    J. Biol. Chem.

    (2002)
  • H.M. Lehmann et al.

    Zinc status influences zinc transport by porcine brain capillary endothelial cells

    J. Nutr.

    (2002)
  • J.P. Liuzzi et al.

    Differential regulation of zinc transporter 1, 2, and 4 mRNA expression by dietary zinc in rats

    J. Nutr.

    (2001)
  • V. Lopantsev et al.

    Lack of vesicular zinc in mossy fibers does not affect synaptic excitability of CA3 pyramidal cells in zinc transporter 3 knockout mice

    Neuroscience

    (2003)
  • W. Maret

    Cellular zinc and redox states converge in the metallothioein/thionein pair

    J. Nutr.

    (2003)
  • J.P. McClung et al.

    The influence of zinc status on the kinetics of zinc uptake into cultured endothelial cells

    J. Nutr. Biochem.

    (1999)
  • B. Milon et al.

    Differential subcellular localization of hZIP1 in adherant and non-adherant cells

    FEBS Lett.

    (2001)
  • P.G. Reeves et al.

    Pretreatment of Caco-2 cells with zinc during the differentiation phase alters the kinetics of zinc uptake and transport

    J. Nutr. Biochem.

    (2001)
  • N.-E.L. Saris et al.

    Is Zn transported by the mitochondrial calcium uniporter

    FEBS Lett.

    (1994)
  • S.L. Sensi et al.

    Mitochondrial sequestration and Ca(2+)-dependent release of cytosolic Zn(2+) loads in cortical neurons

    Neurobiol. Dis.

    (2002)
  • C.T. Sheline et al.

    Depolarization-induced 65zinc influx into cultured cortical neurons

    Neurobiol. Dis.

    (2002)
  • V. Snitsarev et al.

    Fluorescent detection of Zn2+-rich vesicles with zinquin: Mechanism of action in lipid environments

    Biophys. J.

    (2001)
  • A. Takeda

    Movement of zinc and its functional significance in the brain

    Brain Res. Rev.

    (2000)
  • S. Tandy et al.

    Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-1 cells

    J. Biol. Chem.

    (2000)
  • K.M. Taylor et al.

    The LZT proteins. The LIV-1 subfamily of zinc transporters

    Biochim. Biophys. Acta

    (2003)
  • R.B. Thompson et al.

    Fluorescent zinc indicators for neurobiology

    J. Neurosci. Methods

    (2002)
  • T. Valente et al.

    Developmental expression of ZnT3 in mouse brain:correlation between the vesicular zinc transporter protein and chelatable vesicular zinc (CVZ) cells. Glial and neuronal CVZ cells interact

    Mol. Cell. Neurosci.

    (2002)
  • E. Aizenman et al.

    Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release

    J. Neurochem.

    (2000)
  • G.K. Andrews

    Cellular zinc sensors: MTF-1 regulation of gene expression

    BioMetals

    (2001)
  • L. Aniksztein et al.

    Selective release of endogenous zinc from the hippocampal mossy fibers in situ

    Brain Res.

    (1987)
  • G.P. Brierley et al.

    Ion transport by heart mitochondria: X. The uptake and release of Zn2+ and its relation to the energy-linked accumulation of magnesium

    Biochemistry

    (1967)
  • S.L. Budd et al.

    Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • S.C. Burdette et al.

    Meeting of the minds: metalloneurochemistry

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • Cited by (160)

    View all citing articles on Scopus
    View full text