Skip to main content
Book cover

Handbook of Neurochemistry and Molecular Neurobiology pp 257–284Cite as

Role and Regulation of Copper and Zinc Transport Proteins in the Central Nervous System

Abstract:

The trace elements copper and zinc are essential for the molecular and physiological functions of the central nervous system (CNS). These cations act as cofactors for enzymes that regulate every aspect of CNS function, including neuronal development and plasticity, neurotransmitter synthesis and processing, cellular metabolism and energy production, and gene expression. Imbalances in zinc have been associated with a variety of clinical disorders, including Alzheimer's disease (AD) and Parkinson's disease. Zinc has also been implicated in the neuronal damage and death associated with ischemia, seizure disorders, and brain trauma. Genetic disorders characterized by copper toxicity and copper deficiency have severe neurological consequences. Thus, it is important that subcellular copper and zinc balance be maintained precisely. This task is accomplished by several families of metal-specific transport proteins. For each metal, this chapter will begin with a brief introduction to the role of this metal in the CNS. This will be followed by the function and regulation of the known transport proteins involved in cellular uptake, intracellular trafficking, and cellular export in the CNS. There will also be discussions of the clinical implications of zinc and copper transporter abnormalities as well as the possible ways that an understanding of these transporters could lead to the development of new treatments for a variety of neurological disorders.

Keywords

  • Zinc Deficiency
  • Zinc Transporter
  • Central Nervous System Function
  • Free Zinc
  • Cellular Zinc

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

This is a preview of subscription content, access via your institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-0-387-30380-2_13
  • Chapter length: 28 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   249.00
Price excludes VAT (USA)
  • ISBN: 978-0-387-30380-2
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Hardcover Book
USD   249.00
Price excludes VAT (USA)
Learn about institutional subscriptions
Figure 13-1
Figure 13-2
Figure 13-3
Figure 13-4
Figure 13-5
Figure 13-6
Figure 13-7
Figure 13-8

Abbreviations

AD:

Alzheimer's disease

AE:

acrodermatitis enteropathica

AMPA:

alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid glutamate receptor

ATP7A:

Menkes protein, MNK

ATP7B:

Wilsons protein, WND

BSE:

bovine spongiform encephalopathy

CCK:

cholecystokinin

CCO:

cytochrome c oxidase

CCS:

copper chaperone for SOD

CJD:

Creutzfeldt‐Jakob disease

CNS:

central nervous system

Cp:

ceruloplasmin

Cu:

copper

DβM:

dopamine beta monooxygenase

DMT1:

divalent metal transporter‐1

FKBP52:

FK506‐binding protein 52

GABA:

gamma‐aminobutyric acid

GABAA :

GABAA receptor

Glu:

glutamate

GnRH:

gonadotropin‐releasing hormone

GPI:

glycosylphosphatidylinositol

LZT:

LIV‐1 subfamily of ZIP zinc transporters

MMP:

matrix metalloproteinase protein

MNK:

Menkes protein, ATP7A

MSH:

melanocortin stimulating hormone

MT:

metallothionein

NMDA:

N‐methyl‐d‐aspartate glutamate receptor

NPY:

neuropeptide Y

NRF:

nuclear respiratory factor

PAM:

peptidylglycine α‐amidating monooxygenase

SOD:

superoxide dismutase

TGN:

trans‐Golgi network

TRH:

thyrotropin‐releasing hormone

VGCaC:

Voltage‐gated calcium channels

VIP:

vasoactive intestinal polypeptide

WND:

Wilsons disease protein, APT7B

ZIP:

Zrt/Irt‐like proteins

Zn:

zinc

ZnT:

zinc transporter

References

  • Acarin L, Gonzalez B, Hidalgo J, Castro AJ, Castellano B. 1999a. Primary cortical glial reaction versus secondary thalamic glial response in the excitotoxically injured young brain: Astroglial response and metallothionein expression. Neuroscience 92: 827–839.

    CAS  Google Scholar 

  • Acarin L, Carrasco J, Gonzalez B, Hidalgo J, Castellano B. 1999b. Expression of growth inhibitory factor (metallothionein-III) mRNA and protein following excitotoxic immature brain injury. J Neuropathol Exp Neurol 58: 389–397.

    CAS  Google Scholar 

  • Ahn YH, Kim YH, Hong SH, Koh JY. 1998. Depletion of intracellular zinc induces protein synthesis-dependent neuronal apoptosis in mouse cortical culture. Exp Neurol 154: 47–56.

    CAS  PubMed  Google Scholar 

  • Amaravadi R, Glerum DM, Tzagoloff A. 1997. Isolation of a cDNA encoding the human homolog of COX17, a yeast gene essential for mitochondrial copper recruitment. Hum Genet 99: 329–333.

    CAS  PubMed  Google Scholar 

  • Amoureux MC, Gool D, Van Herrero MT, Dom R, Colpaertet FC et al. 1997. Regulation of metallothionein-III (GIF) mRNA in the brain of patients with Alzheimer disease is not impaired. Mol Chem Neuropathol 32: 101–121.

    CAS  PubMed  Google Scholar 

  • Andrews GK. 1990. Regulation of metallothionein gene expression. Prog Food Nutr Sci 14: 193–258.

    CAS  PubMed  Google Scholar 

  • Andrews RC. 1992. An update of the zinc deficiency theory of schizophrenia. Identification of the sex determining system as the site of action of reproductive zinc deficiency. Med Hypotheses 38: 284–291.

    CAS  PubMed  Google Scholar 

  • Assaf SY, Chung SH. 1984. Release of endogenous Zn2+ from brain tissue during activity. Nature 308: 734–736.

    CAS  PubMed  Google Scholar 

  • Bankier A. 1995. Menkes disease. J Med Genet 32: 213–215.

    CAS  PubMed  Google Scholar 

  • Barros MH, Johnson A, Tzagoloff A. 2004. COX23, a homologue of COX17, is required for cytochrome oxidase assembly. J Biol Chem 279: 31943–31947.

    CAS  PubMed  Google Scholar 

  • Bayer TA, Schafer S, Simons A, Kemmling A, Kamer T, et al. 2003. Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci USA 100: 14187–14192.

    CAS  PubMed  Google Scholar 

  • Bellingham SA, Lahiri DK, Maloney B, La Fontaine S, Multhaup G, et al. 2004. Copper depletion down-regulates expression of the Alzheimer's disease amyloid-beta precursor protein gene. J Biol Chem 279: 20378–20386.

    CAS  PubMed  Google Scholar 

  • Berg JM, Shi Y. 1996. The galvanization of biology: A growing appreciation for the roles of zinc. Science 271: 1081–1085.

    CAS  PubMed  Google Scholar 

  • Bertinato J, L'Abbe MR. 2003. Copper modulates the degradation of copper chaperone for Cu,Zn superoxide dismutase by the 26 S proteosome. J Biol Chem 278: 35071–35078.

    CAS  PubMed  Google Scholar 

  • Bertinato J, Iskandar M, L'Abbe MR. 2003. Copper deficiency induces the upregulation of the copper chaperone for Cu/Zn superoxide dismutase in weanling male rats. J Nutr 133: 28–31.

    CAS  PubMed  Google Scholar 

  • Biasio W, Chang T, McIntosh CJ, McDonald FJ. 2004. Identification of Murr1 as a regulator of the human delta epithelial sodium channel. J Biol Chem 279: 5429–5434.

    CAS  PubMed  Google Scholar 

  • Blaauwgeers HG, Sillevis Smitt PA, De Jong JM, Troost D. 1993. Distribution of metallothionein in the human central nervous system. Glia 8: 62–70.

    CAS  PubMed  Google Scholar 

  • Black MM. 2003. The evidence linking zinc deficiency with children's cognitive and motor functioning. J Nutr 133: 1473S–1476S.

    CAS  PubMed  Google Scholar 

  • Blakemore LJ, Trombley PQ. 2004. Diverse modulation of olfactory bulb AMPA receptors by zinc. Neuroreport 15: 919–923.

    CAS  PubMed  Google Scholar 

  • Borjigin J, Payne AS, Deng J, Li X, Wang MM, et al. 1999. A novel pineal night-specific ATPase encoded by the Wilson disease gene. J Neurosci 19: 1018–1026.

    CAS  PubMed  Google Scholar 

  • Brandao-Neto J, Madureira G, Mendonca BB, Bloise W, Castro AV. 1995. Endocrine interaction between zinc and prolactin. An interpretative review. Biol Trace Elem Res 49: 139–149.

    CAS  Google Scholar 

  • Brown DR. 2004. Role of the prion protein in copper turnover in astrocytes. Neurobiol Dis 15: 534–543.

    CAS  PubMed  Google Scholar 

  • Brown S, Coghill ID, McGrath MJ, Robinson PA. 2001. Role of LIM domains in mediating signaling protein interactions. IUBMB Life 51: 359–364.

    CAS  PubMed  Google Scholar 

  • Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. 1993. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5: 327–337.

    CAS  PubMed  Google Scholar 

  • Carrasco J, Penkowa M, Hadberg H, Molinero A, Hidalgo J. 2000. Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I + II-deficient mice. Eur J Neurosci 12: 2311–2322.

    CAS  PubMed  Google Scholar 

  • Carrasco J, Penkowa M, Giralt M, Camats J, Molinero A, et al. 2003. Role of metallothionein-III following central nervous system damage. Neurobiol Dis 13: 22–36.

    CAS  PubMed  Google Scholar 

  • Casareno RL, Waggoner D, Gitlin JD. 1998. The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase. J Biol Chem 273: 23625–23628.

    CAS  PubMed  Google Scholar 

  • Castelli L, Tanzi F, Taglietti V, Magistretti J. 2003. Cu2+, Co2+, and Mn2+ modify the gating kinetics of high-voltage-activated Ca2+ channels in rat palaeocortical neurons. J Membr Biol 195: 121–136.

    CAS  PubMed  Google Scholar 

  • Cater MA, Forbes J, La Fontaine S, Cox D, Mercer JF. 2004. Intracellular trafficking of the human Wilson protein: The role of the six N-terminal metal-binding sites. Biochem J 380: 805–813.

    CAS  PubMed  Google Scholar 

  • Chelly J, Tumer Z, Tonnesen T, Petterson A, Ishikawa-Brush Y, et al. 1993. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet 3: 14–19.

    CAS  PubMed  Google Scholar 

  • Chung RS, Vickers JC, Chuah MI, Eckhardt BL, West AK. 2002. Metallothionein-III inhibits initial neurite formation in developing neurons as well as postinjury, regenerative neurite sprouting. Exp Neurol 178: 1–12.

    CAS  PubMed  Google Scholar 

  • Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD. 1999. Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci USA 96: 1716–1721.

    CAS  PubMed  Google Scholar 

  • Colvin RA, Davis N, Nipper RW, Carter PA. 2000. Evidence for a zinc/proton antiporter in rat brain. Neurochem Int 36: 539–547.

    CAS  PubMed  Google Scholar 

  • Colvin RA, Fontaine CP, Laskowski M, Thomas D. 2003. Zn2+ transporters and Zn2+ homeostasis in neurons. Eur J Pharmacol 479: 171–185.

    CAS  PubMed  Google Scholar 

  • Corson LB, Strain JJ, Culotta VC, Cleveland DW. 1998. Chaperone-facilitated copper binding is a property common to several classes of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants. Proc Natl Acad Sci USA 95: 6361–6366.

    CAS  PubMed  Google Scholar 

  • Cousins RJ, McMahon RJ. 2000. Integrative aspects of zinc transporters. J Nutr 130: 1384S–1387S.

    CAS  PubMed  Google Scholar 

  • Cousins RJ, Blanchard RK, Popp MP, Liu L, Cao J, et al. 2003. A global view of the selectivity of zinc deprivation and excess on genes expressed in human THP-1 mononuclear cells. Proc Natl Acad Sci USA 100: 6952–6957.

    CAS  PubMed  Google Scholar 

  • Cragg RA, Christie GR, Phillips SR, Russi RM, Kury S, et al. 2002. A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane. J Biol Chem 277: 22789–22797.

    CAS  PubMed  Google Scholar 

  • Crocker SJ, Pagenstecher A, Campbell IL. 2004. The TIMPs tango with MMPs and more in the central nervous system. J Neurosci Res 75: 1–11.

    CAS  PubMed  Google Scholar 

  • Cuajungco MP, Lees GJ. 1997. Zinc metabolism in the brain: Relevance to human neurodegenerative disorders. Neurobiol Dis 4: 137–169.

    CAS  PubMed  Google Scholar 

  • Culotta VC, Klomp LW, Strain J, Casareno RL, Krems B, et al. 1997. The copper chaperone for superoxide dismutase. J Biol Chem 272: 23469–23472.

    CAS  PubMed  Google Scholar 

  • Danks DM, Campell P, Stevens BJ, Howell RR. 1972. Menkes’ kinky hair syndrome: An inherited defect of copper absorption with widespread effects. Pediatrics 50: 188–201.

    CAS  PubMed  Google Scholar 

  • Danscher G. 1996. The autometallographic zinc-sulphide method. A new approach involving in vivo creation of nanometer-sized zinc sulphide crystal lattices in zinc-enriched synaptic and secretory vesicles. Histochem J 28: 361–373.

    CAS  PubMed  Google Scholar 

  • Das S, Levinson B, Whitney S, Vulpe C, Packman S, et al. 1994. Diverse mutations in patients with Menkes disease often lead to exon skipping. Am J Hum Genet 55: 883–889.

    CAS  PubMed  Google Scholar 

  • Dufner-Beattie J, Langmade SJ, Wang F, Eide D, Andrews GK. 2003. Structure, function, and regulation of a subfamily of mouse zinc transporter genes. J Biol Chem 278: 50142–50150.

    CAS  PubMed  Google Scholar 

  • Ebadi M, Iversen PL, Hao R, Cerutis DR, Rojas P, et al. 1995. Expression and regulation of brain metallothionein. Neurochem Int 27: 1–22.

    CAS  PubMed  Google Scholar 

  • Eide DJ. 2000. Metal ion transport in eukaryotic microorganisms: Insights from Saccharomyces cerevisiae. Adv Microb Physiol 43: 1–38.

    CAS  PubMed  Google Scholar 

  • Eisses JF, Kaplan JH. 2002. Molecular characterization of hCTR1, the human copper uptake protein. J Biol Chem 277: 29162–29171.

    CAS  PubMed  Google Scholar 

  • Erway LC, Grider A, Jr. 1984. Zinc metabolism in lethal-milk mice. Otolith, lactation, and aging effects. J Hered 75: 480–484.

    CAS  PubMed  Google Scholar 

  • Ferenci P. 2004. Review article: Diagnosis and current therapy of Wilson's disease. Aliment Pharmacol Ther 19: 157–165.

    CAS  PubMed  Google Scholar 

  • Field LS, Luk E, Culotta VC. 2002. Copper chaperones: Personal escorts for metal ions. J Bioenerg Biomembr 34: 373–379.

    CAS  PubMed  Google Scholar 

  • Foltopoulou PF, Zachariadis GA, Politou AS, Tsiftsoglou AS, Papadopoulou LC. 2004. Human recombinant mutated forms of the mitochondrial COX assembly Sco2 protein differ from wild-type in physical state and copper binding capacity. Mol Genet Metab 81: 225–236.

    CAS  PubMed  Google Scholar 

  • Forbes JR, Cox DW. 2000. Copper-dependent trafficking of Wilson disease mutant ATP7B proteins. Hum Mol Genet 9: 1927–1935.

    CAS  PubMed  Google Scholar 

  • Francis MJ, Jones EE, Levy ER, Ponnambalam S, Chelly J, et al. 1998. A Golgi localization signal identified in the Menkes recombinant protein. Hum Mol Genet 7: 1245–1252.

    CAS  PubMed  Google Scholar 

  • Franco-Pons N, Casanovas-Aguilar C, Arroyo S, Rumia J, Perez-Clausell J, et al. 2000. Zinc-rich synaptic boutons in human temporal cortex biopsies. Neuroscience 98: 429–435.

    CAS  PubMed  Google Scholar 

  • Frederickson CJ, Bush AI. 2001. Synaptically released zinc: Physiological functions and pathological effects. Biometals 14: 353–366.

    CAS  PubMed  Google Scholar 

  • Frederickson CJ, Suh SW, Silva D, Frederickson CJ, Thompson RB. 2000. Importance of zinc in the central nervous system: The zinc-containing neuron. J Nutr 130: 1471S–1483S.

    CAS  PubMed  Google Scholar 

  • Freisinger P, Horvath R, Macmillan C, Peters J, Jaksch M. 2004. Reversion of hypertrophic cardiomyopathy in a patient with deficiency of the mitochondrial copper binding protein Sco2: Is there a potential effect of copper? J Inherit Metab Dis 27: 67–79.

    CAS  PubMed  Google Scholar 

  • Gaither LA, Eide DJ. 2001. The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J Biol Chem 276: 22258–22264.

    CAS  PubMed  Google Scholar 

  • Ganesh L, Burstein E, Guha-Niyogi A, Louder MK, Mascola JR, et al. 2003. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 426: 853–857.

    CAS  PubMed  Google Scholar 

  • Gitlin JD. 2003. Wilson disease. Gastroenterol 125: 1868–1877.

    Google Scholar 

  • Glerum DM, Shtanko A, Tzagoloff A. 1996.Characterization of COX17, a yeast gene involved in copper metabolism and assembly of cytochrome oxidase. J Biol Chem 271: 14504–14509.

    CAS  PubMed  Google Scholar 

  • Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, et al. 1997. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388: 482–488.

    CAS  PubMed  Google Scholar 

  • Gybina AA, Prohaska JR. 2003. Increased rat brain cytochrome c correlates with degree of perinatal copper deficiency rather than apoptosis. J Nutr 133: 3361–3368.

    CAS  PubMed  Google Scholar 

  • Hamza I, Gitlin JD. 2002. Copper chaperones for cytochrome c oxidase and human disease. J Bioenerg Biomembr 34: 381–388.

    CAS  PubMed  Google Scholar 

  • Hamza I, Schaefer M, Klomp LW, Gitlin JD. 1999. Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis. Proc Natl Acad Sci USA 96: 13363–13368.

    CAS  PubMed  Google Scholar 

  • Hamza I, Klomp LW, Gaedigk R, White RA, Gitlin JD. 2000. Structure, expression, and chromosomal localization of the mouse Atox1 gene. Genomics 63: 294–297.

    CAS  PubMed  Google Scholar 

  • Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, et al. 2001. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci USA 98: 6848–6852.

    CAS  PubMed  Google Scholar 

  • Hamza I, Prohaska J, Gitlin JD. 2003. Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase. Proc Natl Acad Sci USA 100: 1215–1220.

    CAS  PubMed  Google Scholar 

  • Harada M, Sakisaka S, Terada K, Kimura R, Kawaguchi T, et al. 2001. A mutation of the Wilson disease protein, ATP7B, is degraded in the proteasomes and forms protein aggregates. Gastroenterol 120: 967–974.

    CAS  Google Scholar 

  • Harada M, Kumemura H, Sakisaka S, Shishido S, Taniguchi E, et al. 2003. Wilson disease protein ATP7B is localized in the late endosomes in a polarized human hepatocyte cell line. Int J Mol Med 11: 293–298.

    CAS  PubMed  Google Scholar 

  • Harrison NL, Gibbons SJ. 1994. Zn2+: An endogenous modulator of ligand- and voltage-gated ion channels. Neuropharmacology 33: 935–952.

    CAS  PubMed  Google Scholar 

  • Hartter DE, Barnea A. 1988. Evidence for release of copper in the brain: Depolarization-induced release of newly taken-up 67copper. Synapse 2: 412–415.

    CAS  PubMed  Google Scholar 

  • Haussler MR, Haussler CA, Jurutka PW, Thompson PD, Hsieh JC, et al. 1997. The vitamin D hormone and its nuclear receptor: Molecular actions and disease states. J Endocrinol 154: S57–S73.

    CAS  PubMed  Google Scholar 

  • Henkin RI, Patten BM, Re PK, Bronzert DA. 1975. A syndrome of acute zinc loss. Cerebellar dysfunction, mental changes, anorexia, and taste and smell dysfunction. Arch Neurol 32: 745–751.

    CAS  Google Scholar 

  • Hidalgo J, Aschner M, Zatta P, Vasak M. 2001. Roles of the metallothionein family of proteins in the central nervous system. Brain Res Bull 55: 133–145.

    CAS  PubMed  Google Scholar 

  • Hijazi N, Shaked Y, Rosenmann H, Ben-Hur T, Gabizon R. 2003. Copper binding to PrPC may inhibit prion disease propagation. Brain Res 993: 192–200.

    CAS  PubMed  Google Scholar 

  • Horng YC, Cobine PA, Maxfield AB, Carr HS, Winge DR. 2004. Specific copper transfer from the cox17 metallochaperone to both sco1 and cox11 in the assembly of yeast cytochrome c oxidase. J Biol Chem 279: 35334–35340.

    CAS  PubMed  Google Scholar 

  • Horning MS, Trombley PQ. 2001. Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms. J Neurophysiol 86: 1652–1660.

    CAS  PubMed  Google Scholar 

  • Hoss W, Formaniak M. 1980. Enhancement of synaptic vesicle attachment to the plasma membrane fraction by copper. Neurochem Res 5: 795–803.

    CAS  PubMed  Google Scholar 

  • Huang L, Gitschier J. 1997. A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nat Genet 17: 292–297.

    CAS  PubMed  Google Scholar 

  • Huang L, Kirschke CP, Gitschier J. 2002. Functional characterization of a novel mammalian zinc transporter, ZnT6. J Biol Chem 277: 26389–26395.

    CAS  PubMed  Google Scholar 

  • Hung IH, Casareno RL, Labesse G, Mathews FS, Gitlin JD. 1998. HAH1 is a copper-binding protein with distinct amino acid residues mediating copper homeostasis and antioxidant defense. J Biol Chem 273: 1749–1754.

    CAS  PubMed  Google Scholar 

  • Hunt DM, Johnson DR. 1972. An inherited deficiency in noradrenaline biosynthesis in the brindled mouse. J Neurochem 12: 2811–2819.

    Google Scholar 

  • Huster D, Hoppert M, Lutsenko S, Zinke J, Lehmann C, et al. 2003. Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines. Gastroenterol 124: 335–345.

    CAS  Google Scholar 

  • Ishida S, Lee J, Thiele DJ, Herskowitz I. 2002. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci USA 99: 14298–14302.

    CAS  PubMed  Google Scholar 

  • Jaksch M, Horvath R, Horn N, Auer DP, Macmillan C, et al. 2001. Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy. Neurology 57: 1440–1446.

    CAS  PubMed  Google Scholar 

  • Jamieson AC, Miller JC, Pabo CO. 2003. Drug discovery with engineered zinc-finger proteins. Nat Rev Drug Discov 2: 361–368.

    CAS  PubMed  Google Scholar 

  • Jeong SY, David S. 2003. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 278: 27144–27148.

    CAS  PubMed  Google Scholar 

  • Jiang LJ, Maret W, Vallee BL. 1998. The ATP-metallothionein complex. Proc Natl Acad Sci USA 95: 9146–9149.

    CAS  PubMed  Google Scholar 

  • Kako K, Tsumori K, Ohmasa Y, Takahashi Y, Munekata E. 2000. The expression of Cox17p in rodent tissues and cells. Eur J Biochem 267: 6699–6707.

    CAS  PubMed  Google Scholar 

  • Kaler SG, Holmes CS, Goldstein DS. 1998. Dopamine beta-hydroxylase deficiency associated with mutations in a copper transporter gene. Adv Pharmacol 42: 66–68.

    CAS  PubMed  Google Scholar 

  • Kambe T, Narita H, Yamaguchi-Iwai Y, Hirose J, Amano T, et al. 2002. Cloning and characterization of a novel mammalian zinc transporter, zinc transporter 5, abundantly expressed in pancreatic beta cells. J Biol Chem 277: 19049–19055.

    CAS  PubMed  Google Scholar 

  • Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M. 2004. Overview of mammalian zinc transporters. Cell Mol Life Sci 61: 49–68.

    CAS  PubMed  Google Scholar 

  • Kardos J, Kovacs I, Hajos F, Kalman M, Simonyi M. 1989. Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability. Neurosci Lett 103: 139–144.

    CAS  Google Scholar 

  • Kelleher SL, Lönnerdal B. 2002. Zinc transporters in the rat mammary gland respond to marginal zinc and vitamin A intakes during lactation. J Nutr 132: 3280–3285.

    CAS  PubMed  Google Scholar 

  • Kelner GS, Lee M, Clark ME, Maciejewski D, McGrath D, et al. 2000. The copper transport protein Atox1 promotes neuronal survival. J Biol Chem 275: 580–584.

    CAS  PubMed  Google Scholar 

  • Kim AH, Sheline CT, Tian M, Higashi T, McMahon RJ, et al. 2000. L-type Ca(2+) channel-mediated Zn(2+) toxicity and modulation by ZnT-1 in PC12 cells. Brain Res 886: 99–107.

    CAS  PubMed  Google Scholar 

  • Kim YH, Kim EY, Gwag BJ, Sohn S, Koh JY. 1999. Zinc-induced cortical neuronal death with features of apoptosis and necrosis: Mediation by free radicals. Neuroscience 89: 175–182.

    CAS  PubMed  Google Scholar 

  • Klomp AE, Tops BB, Denberg IE, Van Berger R, Klomp LW. 2002. Biochemical characterization and subcellular localization of human copper transporter 1 (hCTR1). Biochem J 364: 497–505.

    CAS  PubMed  Google Scholar 

  • Klomp AE, Juijn JA, der Gun LT, van den Berg IE, van Berger R, et al. 2003a. The N-terminus of the human copper transporter 1 (hCTR1) is localized extracellularly, and interacts with itself. Biochem J 370: 881–889.

    CAS  Google Scholar 

  • Klomp AE, de Sluis B, van Klomp LW, Wijmenga C. 2003b. The ubiquitously expressed MURR1 protein is absent in canine copper toxicosis. J Hepatol 39: 703–709.

    CAS  Google Scholar 

  • Klomp LW, Gitlin JD. 1996. Expression of the ceruloplasmin gene in the human retina and brain: Implications for a pathogenic model in aceruloplasminemia. Hum Mol Genet 5: 1989–1996.

    CAS  PubMed  Google Scholar 

  • Klomp LW, Lin SJ, Yuan DS, Klausner RD, Culotta VC, et al. 1997. Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. J Biol Chem 272: 9221–9226.

    CAS  PubMed  Google Scholar 

  • Klug A, Schwabe JW. 1995. Protein motifs 5. Zinc fingers. FASEB J 9: 597–604.

    CAS  PubMed  Google Scholar 

  • Kodama H. 1993. Recent developments in Menkes disease. J Inherit Metab Dis 16: 791–799.

    CAS  PubMed  Google Scholar 

  • Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, et al. 1996. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272: 1013–1016.

    CAS  PubMed  Google Scholar 

  • Kohler LB, Berezin V, Bock E, Penkowa M. 2003. The role of metallothionein II in neuronal differentiation and survival. Brain Res 992: 128–136.

    CAS  PubMed  Google Scholar 

  • Komatsu Y, Ogra Y, Suzuki KT. 2002. Copper balance and ceruloplasmin in chronic hepatitis in a Wilson disease animal model, LEC rats. Arch Toxicol 76: 502–508.

    CAS  PubMed  Google Scholar 

  • Kovacs KJ, Larson AA. 1997. Zn2+ inhibition of [3H]MK-801 binding is different in mouse brain and spinal cord: Effect of glycine and glutamate. Eur J Pharmacol 324: 117–123.

    CAS  PubMed  Google Scholar 

  • Kroncke KD, Carlberg C. 2000. Inactivation of zinc finger transcription factors provides a mechanism for a gene regulator role of nitric oxide. FASEB J 14: 166–173.

    CAS  PubMed  Google Scholar 

  • Kuo YM, Gitschier J, Packman S. 1997. Developmental expression of the mouse mottled and toxic milk genes suggests distinct functions for the Menkes and Wilson disease copper transporters. Hum Mol Genet 6: 1043–1049.

    CAS  PubMed  Google Scholar 

  • Kuo YM, Zhou B, Cosco D, Gitschier J. 2001. The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci USA 98: 6836–6841.

    CAS  PubMed  Google Scholar 

  • Kury S, Kharfi M, Kamoun R, Taieb A, Mallet E, et al. 2003. Mutation spectrum of human SLC39A4 in a panel of patients with acrodermatitis enteropathica. Hum Mutat 22: 337–338.

    PubMed  Google Scholar 

  • Laity JH, Lee BM, Wright PE. 2001. Zinc finger proteins: New insights into structural and functional diversity. Curr Opin Struct Biol 11: 39–46.

    CAS  PubMed  Google Scholar 

  • Labbe S, Thiele DJ. 1999. Pipes and wiring: The regulation of copper uptake and distribution in yeast. Trends Microbiol 7: 500–505.

    CAS  PubMed  Google Scholar 

  • Larin D, Mekios C, Das K, Ross B, Yang AS, et al. 1999. Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperone, HAH1p. J Biol Chem 274: 28497–28504.

    CAS  PubMed  Google Scholar 

  • Law W, Kelland EE, Sharp P, Toms NJ. 2003. Characterisation of zinc uptake into rat cultured cerebrocortical oligodendrocyte progenitor cells. Neurosci Lett 352: 113–116.

    CAS  PubMed  Google Scholar 

  • Leary SC, Kaufman BA, Pellecchia G, Guercin GH, Mattman A, et al. 2004. Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase. Hum Mol Genet 13: 1839–1848.

    CAS  PubMed  Google Scholar 

  • Lee J, Prohaska JR, Dagenais SL, Glover TW, Thiele DJ. 2000b Isolation of a murine copper transporter gene, tissue specific expression and functional complementation of a yeast copper transport mutant. Gene 254: 87–96.

    CAS  Google Scholar 

  • Lee J, Prohaska JR, Thiele DJ. 2001b. Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc Natl Acad Sci USA 98: 6842–6847.

    CAS  Google Scholar 

  • Lee J, Pena MM, Nose Y, Thiele DJ. 2002a. Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 277: 4380–4387.

    CAS  Google Scholar 

  • Lee J, Petris MJ, Thiele DJ. 2002b. Characterization of mouse embryonic cells deficient in the ctr1 high affinity copper transporter. Identification of a Ctr1-independent copper transport system. J Biol Chem 277: 40253–40259.

    CAS  Google Scholar 

  • Lee JY, Cole TB, Palmiter RD, Koh JY. 2000a. Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null mice after seizures: Evidence against synaptic vesicle origin. J Neurosci 20: RC79.

    CAS  Google Scholar 

  • Lee JY, Kim JH, Hong SH, Lee JY, Cherny RA, et al. 2004. Estrogen decreases zinc transporter 3 expression and synaptic vesicle zinc levels in mouse brain. J Biol Chem 279: 8602–8607.

    CAS  PubMed  Google Scholar 

  • Lee M, Hyun D, Jenner P, Halliwell B. 2001a. Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative damage and antioxidant defences: Relevance to Down's syndrome and familial amyotrophic lateral sclerosis. J Neurochem 76: 957–965.

    CAS  Google Scholar 

  • Levinson B, Vulpe C, Elder B, Martin C, Verley F, et al. 1994. The mottled gene is the mouse homologue of the Menkes disease gene. Nat Genet 6: 369–373.

    CAS  PubMed  Google Scholar 

  • Li YV, Hough CJ, Sarvey JM. 2003. Do we need zinc to think? Sci STKE 182: pe19.

    Google Scholar 

  • Lin DD, Cohen AS, Coulter DA. 2001. Zinc-induced augmentation of excitatory synaptic currents and glutamate receptor responses in hippocampal CA3 neurons. J Neurophysiol 85: 1185–1196.

    CAS  PubMed  Google Scholar 

  • Liuzzi JP, Cousins RJ. 2004. Mammalian zinc transporters. Annu Rev Nutr 24: 151–172.

    CAS  PubMed  Google Scholar 

  • Liuzzi JP, Blanchard RK, Cousins RJ. 2001. Differential regulation of zinc transporter 1, 2, and 4 mRNA expression by dietary zinc in rats. J Nutr 131: 46–52.

    CAS  PubMed  Google Scholar 

  • Lutsenko S, Cooper MJ. 1998. Localization of the Wilson's disease protein product to mitochondria. Proc Natl Acad Sci USA 95: 6004–6009.

    CAS  PubMed  Google Scholar 

  • Lutsenko S, Tsivkovskii R, Walker JM. 2003. Functional properties of the human copper-transporting ATPase ATP7B (the Wilson's disease protein) and regulation by metallochaperone Atox1. Ann N Y Acad Sci 986: 204–211.

    CAS  PubMed  Google Scholar 

  • Maes M, D'Haese PC, Scharpe S, D'Hondt P, Cosyns P, et al. 1994. Hypozincemia in depression. J Affect Disord 31: 135–140.

    CAS  PubMed  Google Scholar 

  • Maes M, De Vos N, Demedts P, Wauters A, Neels H. 1999. Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J Affect Disord 56: 189–194.

    CAS  PubMed  Google Scholar 

  • Maier CM, Chan PH. 2002. Role of superoxide dismutases in oxidative damage and neurodegenerative disorders. Neuroscientist 8: 323–334.

    CAS  PubMed  Google Scholar 

  • Martinez-Galan JR, Diaz C, Juiz JM. 2003. Histochemical localization of neurons with zinc-permeable AMPA/kainate channels in rat brain slices. Brain Res 963: 156–164.

    CAS  PubMed  Google Scholar 

  • Masters BA, Quaife CJ, Erickson JC, Kelly EJ, Froelick GJ, et al. 1994. Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles. J Neurosci 14: 5844–5857.

    CAS  PubMed  Google Scholar 

  • Maxfield AB, Heaton DN, Winge DR. 2004. Cox17 is functional when tethered to the mitochondrial inner membrane. J Biol Chem 279: 5072–5080.

    CAS  PubMed  Google Scholar 

  • Maynard CJ, Cappai R, Volitakis I, Cherny RA, White AR, et al. 2002. Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron. J Biol Chem 277: 44670–44676.

    CAS  PubMed  Google Scholar 

  • McCall KA, Huang C, Fierke CA. 2000. Function and mechanism of zinc metalloenzymes. J Nutr 130: 1437S–1446S.

    CAS  PubMed  Google Scholar 

  • McMahon RJ, Cousins RJ. 1998. Mammalian zinc transporters. J Nutr 128: 667–670.

    CAS  PubMed  Google Scholar 

  • Menkes JH. 1988. Kinky hair disease: Twenty-five years later. Brain Dev 10: 77–79.

    CAS  PubMed  Google Scholar 

  • Menkes JH, Alter M, Steigleder GK, Weakley DR, Sung JH. 1962. A sex-linked recessive disorder with retardation of growth, peculiar hair and focal cerebral and cerebellar degeneration. Pediatrics 29: 764–779.

    CAS  PubMed  Google Scholar 

  • Mercer JF, Livingston J, Hall B, Paynter JA, Begy C, et al. 1993. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nat Genet 3: 20–25.

    CAS  PubMed  Google Scholar 

  • Naeve GS, Vana AM, Eggold JR, Kelner GS, Maki R, et al. 1999. Expression profile of the copper homeostasis gene, rAtox1, in the rat brain. Neuroscience 93: 1179–1187.

    CAS  PubMed  Google Scholar 

  • Narayanan VS, Fitch CA, Levenson CW. 2001. Tumor suppressor protein p53 mRNA and subcellular localization are altered by changes in cellular copper in human Hep G2 cells. J Nutr 131: 1427–1432.

    CAS  PubMed  Google Scholar 

  • Nishihara E, Furuyama T, Yamashita S, Mori N. 1998. Expression of copper trafficking genes in the mouse brain. Neuroreport 9: 3259–3263.

    CAS  PubMed  Google Scholar 

  • Nitzan YB, Sekler I, Hershfinkel M, Moran A, Silverman WF. 2002. Postnatal regulation of ZnT-1 expression in the mouse brain. Brain Res Dev Brain Res 137: 149–157.

    CAS  PubMed  Google Scholar 

  • O'Halloran TV. 1993. Transition metals in control of gene expression. Science 261: 715–725.

    PubMed  Google Scholar 

  • Ohana E, Segal D, Palty R, Ton-That D, Moran A, et al. 2004. A sodium zinc exchange mechanism is mediating extrusion of zinc in mammalian cells. J Biol Chem 279: 4278–4284.

    CAS  PubMed  Google Scholar 

  • Orrell RW, Marklund SL, de Belleroche JS. 1997. Familial ALS is associated with mutations in all exons of SOD1: A novel mutation in exon 3 (Gly72Ser). J Neurol Sci 153: 46–49.

    CAS  PubMed  Google Scholar 

  • Palmiter RD, Findley SD, Whitmore TE, Durnam DM. 1992. MT-III, a brain-specific member of the metallothionein gene family. Proc Natl Acad Sci USA 89: 6333–6337.

    CAS  PubMed  Google Scholar 

  • Palmiter RD, Findley SD. 1995. Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J 14: 639–649.

    CAS  PubMed  Google Scholar 

  • Palmiter RD, Cole TB, Quaife CJ, Findley SD. 1996. ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci USA 93: 14934–14939.

    CAS  PubMed  Google Scholar 

  • Palmiter RD, Huang L. 2004. Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch 447: 744–751.

    CAS  PubMed  Google Scholar 

  • Palumaa P, Kangur L, Voronova A, Sillard R. 2004. Metal-binding mechanism of Cox17, a copper chaperone for cytochrome c oxidase. Biochem J 382: 307–314.

    CAS  PubMed  Google Scholar 

  • Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, et al. 2002. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J Neurosci 22: 6578–6586.

    CAS  PubMed  Google Scholar 

  • Payne AS, Kelly EJ, Gitlin JD. 1998. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation. Proc Natl Acad Sci USA 95: 10854–10859.

    CAS  PubMed  Google Scholar 

  • Perafan-Riveros C, Franca LF, Alves AC, Sanches JA Jr. 2002. Acrodermatitis enteropathica: Case report and review of the literature. Pediatr Dermatol 19: 426–431.

    PubMed  Google Scholar 

  • Petris MJ, Camakaris J, Greenough M, La Fontaine S, Mercer JF. 1998. A C-terminal di-leucine is required for localization of the Menkes protein in the trans-Golgi network. Hum Mol Genet 7: 2063–2071.

    CAS  PubMed  Google Scholar 

  • Petris MJ, Strausak D, Mercer JF. 2000. The Menkes copper transporter is required for the activation of tyrosinase. Hum Mol Genet 9: 2845–2851.

    CAS  PubMed  Google Scholar 

  • Petris MJ, Smith K, Lee J, Thiele DJ. 2003. Copper-stimulated endocytosis and degradation of the human copper transporter. J Biol Chem 278: 9639–9646.

    CAS  PubMed  Google Scholar 

  • Petrukhin K, Pirastu M, Tanzi RE, Chernov I, Devoto M, et al. 1993. Mapping cloning and genetic characterization of the region containing the Wilson disease gene. Nat Gen 5: 338–343.

    CAS  Google Scholar 

  • Prasad AS. 2001a. Discovery of human zinc deficiency: Impact on human health. Nutrition 17: 685–687.

    CAS  Google Scholar 

  • Prasad AS. 2001b. Recognition of zinc-deficiency syndrome. Nutrition 17: 67–69.

    CAS  Google Scholar 

  • Prigge ST, Mains RE, Eipper BA, Amzel LM. 2000. New insights into copper monooxygenases and peptide amidation: Structure, mechanism and function. Cell Mol Life Sci 57: 1236–1259.

    CAS  PubMed  Google Scholar 

  • Prohaska, JR, Gybina AA. 2004. Intracellular copper transport in mammals. J Nutr 134: 1003–1006.

    CAS  PubMed  Google Scholar 

  • Prohaska JR, Broderius M, Brokate B. 2003a. Metallochaperone for Cu,Zn-superoxide dismutase (CCS) protein but not mRNA is higher in organs from copper-deficient mice and rats. Arch Biochem Biophys 417: 227–234.

    CAS  Google Scholar 

  • Prohaska JR, Geissler J, Brokate B, Broderius M. 2003b. Copper, zinc-superoxide dismutase protein but not mRNA is lower in copper-deficient mice and mice lacking the copper chaperone for superoxide dismutase. Exp Biol Med 228: 959–966.

    CAS  Google Scholar 

  • Qi M, Byers PH. 1998. Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the menkes protein and produces the occipital horn syndrome. Hum Mol Genet 7: 465–469.

    CAS  PubMed  Google Scholar 

  • Qian Y, Tiffany-Castiglioni E, Harris ED. 1997. A Menkes P-type ATPase involved in copper homeostasis in the central nervous system of the rat. Brain Res Mol Brain Res 48: 60–66.

    CAS  PubMed  Google Scholar 

  • Radja N, Charles-Holmes R. 2002. Acrodermatitis enteropathica—lifelong follow-up and zinc monitoring. Clin Exp Dermatol 27: 62–63.

    CAS  PubMed  Google Scholar 

  • Reddy MC, Harris ED. 1998. Multiple transcripts coding for the menkes gene: Evidence for alternative splicing of Menkes mRNA. Biochem J 334: 71–77.

    CAS  PubMed  Google Scholar 

  • Roelofsen H, Wolters H, Luyn MJ, Van Miura N, Kuipers F, et al. 2000. Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterol 119: 782–793.

    CAS  Google Scholar 

  • Rothstein JD, Dykes-Hoberg M, Corson LB, Becker M, Cleveland DW, et al. 1999. The copper chaperone CCS is abundant in neurons and astrocytes in human and rodent brain. J Neurochem 72: 422–429.

    CAS  PubMed  Google Scholar 

  • Sacher A, Cohen A, Nelson N. 2001. Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes. J Exp Biol 204: 1053–1061.

    CAS  PubMed  Google Scholar 

  • Saito T, Okabe M, Hosokawa T, Kurasaki M, Hata A, et al. 1999. Immunohistochemical determination of the Wilson Copper-transporting P-type ATPase in the brain tissues of the rat. Neurosci Lett 266: 13–16.

    CAS  PubMed  Google Scholar 

  • Saito T, Takahashi K, Nakagawa N, Hosokawa T, Kurasaki M, et al. 2000. Deficiencies of hippocampal Zn and ZnT3 accelerate brain aging of Rat. Biochem Biophys Res Commun 279: 505–511.

    CAS  PubMed  Google Scholar 

  • Salviati L, Hernandez-Rosa E, Walker WF, Sacconi S, Di Mauro S, et al. 2002. Copper supplementation restores cytochrome c oxidase activity in cultured cells from patients with SCO2 mutations. Biochem J 363: 321–327.

    CAS  PubMed  Google Scholar 

  • Sanokawa-Akakura R, Dai H, Akakura S, Weinstein D, Fajardo JE, et al. 2004. A novel role for the immunophilin FKBP52 in copper transport. J Biol Chem 279: 27845–27848.

    CAS  PubMed  Google Scholar 

  • Saris NE, Niva K. 1994. Is Zn2+ transported by the mitochondrial calcium uniporter? FEBS Lett 356: 195–198.

    CAS  PubMed  Google Scholar 

  • Savouret JF, Chauchereau A, Misrahi M, Lescop P, Mantel A, et al. 1994. The progesterone receptor. Biological effects of progestins and antiprogestins. Hum Reprod 9: 7–11.

    CAS  Google Scholar 

  • Scarpulla RC. 1997. Nuclear control of respiratory chain expression in mammalian cells. J Bioenerg Biomembr 29: 109–119.

    CAS  PubMed  Google Scholar 

  • Schaefer M, Roelofsen H, Wolters H, Hofmann WJ, Muller M, et al. 1999. Localization of the Wilson's disease protein in human liver. Gastroenterology 117: 1380–1385.

    CAS  PubMed  Google Scholar 

  • Scheinberg IH, Gitlin D. 1952. Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson's disease). Science 116: 484–485.

    CAS  PubMed  Google Scholar 

  • Sekler I, Moran A, Hershfinkel M, Dori A, Margulis A, et al. 2002. Distribution of the zinc transporter ZnT-1 in comparison with chelatable zinc in the mouse brain. J Comp Neurol 447: 201–209.

    CAS  PubMed  Google Scholar 

  • Sensi SL, Canzoniero LM, Yu SP, Ying HS, Koh JY, et al. 1997. Measurement of intracellular free zinc in living cortical neurons: Routes of entry. J Neurosci 17: 9554–9564.

    CAS  PubMed  Google Scholar 

  • Shah AB, Chernov I, Zhang HT, Ross BM, Das K, et al. 1997. Identification and analysis of mutations in the Wilson disease gene (ATP7B): Population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet 61: 317–328.

    CAS  PubMed  Google Scholar 

  • Sharp PA. 2003. Ctr1 and its role in body copper homeostasis. Int J Biochem Cell Biol 35: 288–291.

    CAS  PubMed  Google Scholar 

  • Shi Y, Berg JM. 1995. Specific DNA-RNA hybrid binding by zinc finger proteins. Science 268: 282–284.

    CAS  PubMed  Google Scholar 

  • Shi YB, Du L, Zheng WJ, Tang WX. 2002. Isolation of GIF from porcine brain and studies of its zinc transfer kinetics with apo-carbonic anhydrase. Biometals 15: 421–427.

    CAS  PubMed  Google Scholar 

  • Shim H, Harris ZL. 2003. Genetic defects in copper metabolism. J Nutr 133: 1527S–1531S.

    CAS  PubMed  Google Scholar 

  • Smart TG, Xie X, Krishek BJ. 1994. Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc. Prog Neurobiol 42: 393–341.

    CAS  PubMed  Google Scholar 

  • Sørensen JC, Mattsson B, Andreasen A, Johansson BB. 1998. Rapid disappearance of zinc positive terminals in focal brain ischemia. Brain Res 812: 265–269.

    PubMed  Google Scholar 

  • Steveson TC, Ciccotosto GD, Ma XM, Mueller GP, Mains RE, et al. 2003. Menkes protein contributes to the function of peptidylglycine alpha-amidating monooxygenase. Endocrinology 144: 188–200.

    CAS  PubMed  Google Scholar 

  • Strausak D, Mercer JF, Dieter HH, Stremmel W, Multhaup G. 2001. Copper in disorders with neurological symptoms: Alzheimer's, Menkes, and Wilson diseases. Brain Res Bull 55: 175–185.

    CAS  PubMed  Google Scholar 

  • Strausak D, Howie MK, Firth SD, Schlicksupp A, Pipkorn R, et al. 2003. Kinetic analysis of the interaction of the copper chaperone Atox1 with the metal binding sites of the Menkes protein. J Biol Chem 278: 20821–20827.

    CAS  PubMed  Google Scholar 

  • Szerdahelyi P, Kasa P. 1986. A highly sensitive method for the histochemical demonstration of copper in normal rat tissues. Histochemistry 85: 349–352.

    CAS  PubMed  Google Scholar 

  • Takahashi Y, Kako K, Kashiwabara S, Takehara A, Inada Y, et al. 2002a. Mammalian copper chaperone Cox17p has an essential role in activation of cytochrome c oxidase and embryonic development. Mol Cell Biol 22: 7614–7621.

    CAS  Google Scholar 

  • Takahashi Y, Kako K, Arai A, Ohishi T, Inada Y, et al. 2002b. Characterization and identification of promoter elements in the mouse COX17 gene. Biochim Biophys Acta 1574: 359–364.

    CAS  Google Scholar 

  • Takeda A. 2000. Movement of zinc and its functional significance in the brain. Brain Res Rev 34: 137–148.

    CAS  PubMed  Google Scholar 

  • Takeda A. 2001. Zinc homeostasis and functions of zinc in the brain. Biometals 14: 343–351.

    CAS  PubMed  Google Scholar 

  • Takeda A, Minami A, Seki Y, Oku N. 2004. Differential effects of zinc on glutamatergic and GABAergic neurotransmitter systems in the hippocampus. J Neurosci Res 75: 225–229.

    CAS  PubMed  Google Scholar 

  • Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, et al. 1993. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Gen 5: 344–350.

    CAS  Google Scholar 

  • Tao TY, Liu F, Klomp L, Wijmenga C, Gitlin JD. 2003. The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein. J Biol Chem 278: 41593–41596.

    CAS  PubMed  Google Scholar 

  • Tapiero H, Tew KD. 2003. Trace elements in human physiology and pathology: Zinc and metallothioneins. Biomed Pharmacother 57: 399–411.

    CAS  PubMed  Google Scholar 

  • Taylor KM, Nicholson RI. 2003. The LZT proteins; the LIV-1 subfamily of zinc transporters. Biochim Biophys Acta 1611: 16–30.

    CAS  PubMed  Google Scholar 

  • Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson RI. 2003. Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J 375: 51–59.

    CAS  PubMed  Google Scholar 

  • Tønder N, Johansen FF, Frederickson CJ, Zimmer J, Diemer NH. 1990. Possible role of zinc in the selective degeneration of dentate hilar neurons after cerebral ischemia in the adult rat. Neurosci Lett 109: 247–252.

    PubMed  Google Scholar 

  • Trombley PQ, Shepherd GM. 1996. Differential modulation by zinc and copper of amino acid receptors from rat olfactory bulb neurons. J Neurophysiol 76: 2536–2546.

    CAS  PubMed  Google Scholar 

  • Trombley PQ, Horning MS, Blakemore LJ. 1998. Carnosine modulates zinc and copper effects on amino acid receptors and synaptic transmission. Neuroreport 9: 3503–3507.

    CAS  PubMed  Google Scholar 

  • Tsuda M, Imaizumi K, Katayama T, Kitagawa K, Wanaka A, et al. 1997. Expression of zinc transporter gene, ZnT-1, is induced after transient forebrain ischemia in the gerbil. J Neurosci 17: 6678–6684.

    CAS  PubMed  Google Scholar 

  • Tucker DM, Sandstead HH. 1984. Neuropsychological function in experimental zinc deficiency in humans. The Neurobiology of Zinc Part B: Deficiency, Toxicity, and Pathology, Vol 11B. Frederickson CJ, Howell GA, Kasarskis EF, editors. New York: Alan R Liss; pp. 139–152.

    Google Scholar 

  • Uchida Y, Takio K, Titani K, Ihara Y, Tomonaga M. 1991. The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein. Neuron 7: 337–347.

    CAS  PubMed  Google Scholar 

  • Udom AO, Brady FO. 1980. Reactivation in vitro of zinc-requiring apo-enzymes by rat liver zinc-thionein. Biochem J 187: 329–335.

    CAS  PubMed  Google Scholar 

  • Valente T, Auladell C. 2002. 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 21: 189–204.

    CAS  Google Scholar 

  • Ho A, Van Ward DM, Kaplan J. 2002. Transition metal transport in yeast. Annu Rev Microbiol 56: 237–261.

    PubMed  Google Scholar 

  • Landingham JW, Van Fitch CA, Levenson CW. 2002. Zinc inhibits the nuclear translocation of the tumor suppressor protein p53 and protects cultured human neurons from copper-induced neurotoxicity. Neuromolecular Med 1: 171–182.

    Google Scholar 

  • Vogt K, Mellor J, Tong G, Nicoll R. 2000. The actions of synaptically released zinc at hippocampal mossy fiber synapses. Neuron 26: 187–196.

    CAS  PubMed  Google Scholar 

  • Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J. 1993. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat Genet 3: 7–13.

    CAS  PubMed  Google Scholar 

  • Waggoner DJ, Drisaldi B, Bartnikas TB, Casareno RL, Prohaska JR, et al. 2000. Brain copper content and cuproenzyme activity do not vary with prion protein expression level. J Biol Chem. 275: 7455–7458.

    CAS  PubMed  Google Scholar 

  • Walker JM, Huster D, Ralle M, Morgan CT, Blackburn NJ, et al. 2004. The N-terminal metal-binding site 2 of the Wilson's disease protein plays a key role in the transfer of copper from Atox1. J Biol Chem 279: 15376–15384.

    CAS  PubMed  Google Scholar 

  • Wang A, Dufner-Beattie J, Kim BE, Petris MJ, Andrews G, et al. 2004a. Zinc-stimulated endocytosis controls activity of the mouse ZIP1 and ZIP3 zinc uptake transporters. J Biol Chem 279: 24631–24639.

    CAS  Google Scholar 

  • Wang F, Kim BE, Dufner-Beattie J, Petris MJ, Andrews G, et al. 2004c. Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter. Hum Mol Genet 13: 563–571.

    CAS  Google Scholar 

  • Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. 2002. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71: 66–73.

    CAS  PubMed  Google Scholar 

  • Wang Y, Joh K, Masuko S, Yatsuki H, Soejima H, et al. 2004b. The mouse Murr1 gene is imprinted in the adult brain, presumably due to transcriptional interference by the antisense-oriented U2af1-rs1 gene. Mol Cell Biol 24: 270–279.

    Google Scholar 

  • Weiss JH, Sensi SL. 2000. Ca2+-Zn2+ permeable AMPA or kainate receptors: Possible key factors in selective neurodegeneration. Trends Neurosci 23: 365–371.

    CAS  PubMed  Google Scholar 

  • Wenzel HJ, Cole TB, Born DE, Schwartzkroin PA, Palmiter RD. 1997. Ultrastructural localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey. Proc Natl Acad Sci USA 94: 12676–12681.

    CAS  PubMed  Google Scholar 

  • Wernimont AK, Yatsunyk LA, Rosenzweig AC. 2004. Binding of copper(I) by the Wilson disease protein and its copper chaperone. J Biol Chem 279: 12269–12276.

    CAS  PubMed  Google Scholar 

  • Westbrook GL, Mayer ML. 1987. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature 328: 640–643.

    CAS  PubMed  Google Scholar 

  • White AR, Multhaup G, Maher F, Bellingham S, Camakaris J, et al. 1999. The Alzheimer's disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures. J Neurosci 19: 9170–9179.

    CAS  PubMed  Google Scholar 

  • Wikstrom M. 2004. Cytochrome c oxidase: 25 years of the elusive proton pump. Biochim Biophys Acta 1655: 241–247.

    CAS  PubMed  Google Scholar 

  • Winegar BD, Lansman JB. 1990. Voltage-dependent block by zinc of single calcium channels in mouse myotubes. J Physiol 425: 563–578.

    CAS  PubMed  Google Scholar 

  • Wong PC, Waggoner D, Subramaniam JR, Tessarollo L, Bartnikas TB, et al. 2000. Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase. Proc Natl Acad Sci USA 97: 2886–2891.

    CAS  PubMed  Google Scholar 

  • Xu B, Koenig RJ. 2004. An RNA-binding domain in the thyroid hormone receptor enhances transcriptional activation. J Biol Chem 279: 33051–33056.

    CAS  PubMed  Google Scholar 

  • Yang XL, Miura N, Kawarada Y, Terada K, Petrukhin K, et al. 1997. Two forms of Wilson disease protein produced by alternative splicing are localized in distinct cellular compartments. Biochem J 326: 897–902.

    CAS  PubMed  Google Scholar 

  • Ye B, Maret W, Vallee BL. 2001. Zinc metallothionein imported into liver mitochondria modulates respiration. Proc Natl Acad Sci USA 98: 2317–2322.

    CAS  PubMed  Google Scholar 

  • Yeiser EC, Lerant AA, Casto RM, Levenson CW. 1999a. Free zinc increases at the site of injury after cortical stab wounds in mature but not immature rat brain. Neurosci Lett 277: 75–78.

    CAS  Google Scholar 

  • Yeiser EC, Fitch CA, Horning MS, Rutkoski N, Levenson CW. 1999b. Regulation of metallothionein-3 mRNA by thyroid hormone in developing rat brain and primary cultures of rat astrocytes and neurons. Brain Res Dev Brain Res 115: 195–200.

    CAS  Google Scholar 

  • Yu WH, Lukiw WJ, Bergeron C, Niznik HB, Fraser PE. 2001. Metallothionein III is reduced in Alzheimer's disease. Brain Res 894: 37–45.

    CAS  PubMed  Google Scholar 

  • Zawia NH. 2003. Transcriptional involvement in neurotoxicity. Toxicol Appl Pharmacol 190: 177–188.

    CAS  PubMed  Google Scholar 

  • Zhang DQ, Ribelayga C, Mangel SC, McMahon DG. 2002. Suppression by zinc of AMPA receptor-mediated synaptic transmission in the retina. J Neurophysiol 88: 1245–1251.

    CAS  PubMed  Google Scholar 

  • Zhou B, Gitschier J. 1997. hCTR1: A human gene for copper uptake identified by complementation in yeast. Proc Natl Acad Sci USA 94: 7481–7486.

    CAS  PubMed  Google Scholar 

  • Zhu HL, Wang DS, Li JS. 2002. Cu2+ suppresses GABA(A) receptor-mediated responses in rat sacral dorsal commissural neurons. Neurosignals 11: 322–328.

    CAS  PubMed  Google Scholar 

Download references

Authors
  1. C. W. Levenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. M. Tassabehji
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, New York, 10962, Orangeburg, USA

    Abel Lajtha

  2. Department of Psychiatry Millhauser Labs, Room MHL‐HN–604A, New York University School of Medicine, 550 First Avenue, N.Y. 10016, New York, USA

    Maarten E. A. Reith Ph.D.

Rights and permissions

Reprints and Permissions

Copyright information

© 2007 Springer Science+Business Media, LLC.

About this entry

Cite this entry

Levenson, C.W., Tassabehji, N.M. (2007). Role and Regulation of Copper and Zinc Transport Proteins in the Central Nervous System. In: Lajtha, A., Reith, M.E.A. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30380-2_13

Download citation