Skip to main content
SpringerLink
Log in

Copper homeostasis in the CNS

A novel link between the NMDA receptor and copper homeostasis in the hippocampus

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Copper is an essential nutrient that plays a fundamental role in the biochemistry of the central nervous system, as evidenced by patients with Menkes disease, a fatal neurodegenerative disorder of childhood resulting from the loss-of-function of a copper-transporting P-type adenosine triphosphatase (ATPase). Despite clinical and experimental data indicating a role for copper in brain function, the mechanisms and timing of the critical events affected by copper remain poorly understood. A novel role for the Menkes ATPase has been identified in the availability of an N-methyl-d-aspartate (NMDA) receptor-dependent, releasable pool of copper in hippocampal neurons, suggesting a unique mechanism linking copper homeostasis and neuronal activation within the central nervous system. This article explores the evidence that copper acts as a modulator of neuronal transmission, and that the release of endogenous copper from neurons may regulate NMDA receptor activity. The relationship between impaired copper homeostasis and neuropathophysiology suggests that impairment of copper efflux could alter neuronal function and thus contribute to rapid neuronal degeneration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Culotta V. C. and Gitlin J. D. (2001). The disorders of copper transport. In: The Metabolic and Molecular Bases of Inherited Diseases, Scriver C. R., Beaudet A. L., Sly W. S., and Valle D., eds., New York: McGraw-Hill, pp. 3105–3126.

    Google Scholar 

  2. Lee J., Pena M. M., Nose Y., and Thiele D. J. (2002) Biochemical characterization of the human copper transporter Ctr1. J. Biol. Chem. 277, 4380–4387.

    Article  PubMed  CAS  Google Scholar 

  3. Lee J., Prohaska J. R., and Thiele D. J. (2001). Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development. Proc. Natl. Acad. Sci. USA 98, 6842–6847.

    Article  PubMed  CAS  Google Scholar 

  4. Kuo Y. M., Zhou B., Cosco D., and Gitschier J. (2001). The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc. Natl. Acad. Sci. USA 98, 6836–6841.

    Article  PubMed  CAS  Google Scholar 

  5. Pena M. M., Lee J., and Thiele D. J. (1999). A delicate balance: homeostatic control of copper uptake and distribution. J. Nutr. 129, 1251–1260.

    PubMed  CAS  Google Scholar 

  6. Rae T., Schmidt P., Pufahl R., Culotta V., and O'Halloran T. (1999). Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284, 805–808.

    Article  PubMed  CAS  Google Scholar 

  7. O'Halloran T. V. and Culotta V. C. (2000) Metallochaperones, an intracellular shuttle service for metal ions. J. Biol. Chem. 275, 25057–25060.

    Article  PubMed  Google Scholar 

  8. Rosenzweig A. C. (2001) Copper delivery by metallochaperone proteins. Acc. Chem. Res. 34, 119–128.

    Article  PubMed  CAS  Google Scholar 

  9. Lin S. J. and Culotta V. C. (1995). The ATX1 gene of Saccharomyces cerevisiae encodes a small metal homeostasis factor that protects cells against reactive oxygen toxicity. Proc. Natl. Acad. Sci. USA 92, 3784–3788.

    Article  PubMed  CAS  Google Scholar 

  10. Glerum D. M., Shtanko A., and Tzagoloff A. (1996). Characterization of COX17, a yeast gene involved in copper metabolism and assembly of cytochrome oxidase. J. Biol. Chem. 271, 14,504–14,509.

    CAS  Google Scholar 

  11. Hamza I., Faisst A., Prohaska J., Chen J., Gruss P., and Gitlin J. D. (2001). The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc. Natl. Acad. Sci. USA 98, 6848–6852.

    Article  PubMed  CAS  Google Scholar 

  12. Payne A. S. and Gitlin J. D. (1998). Functional expression of the menkes disease protein reveals common biochemical mechanisms among the copper-transporting P-type ATPases. J. Biol. Chem. 273, 3765–3770.

    Article  PubMed  CAS  Google Scholar 

  13. Hirayama T., Kieber J. J., Hirayama N., et al. (1999). RESPONSIVE-TO-ANTAGONIST1, a Menkes/Wilson disease-related copper transporter, is required for ethylene signaling in Arabidopsis. Cell 97, 383–393.

    Article  PubMed  CAS  Google Scholar 

  14. Rensing C., Fan B., Sharma R., Mitra B., and Rosen B. P. (2000). CopA: An Escherichia coli Cu(I)-translocating P-type ATPase. Proc. Natl. Acad. Sci. USA 97, 652–656.

    Article  PubMed  CAS  Google Scholar 

  15. Yuan D. S., Stearman R., Dancis A., Dunn T., Beeler T., and Klausner R. D. (1995). The Menkes/Wilson disease gene homologue in yeast provides copper to a ceruloplasmin-like oxidase required for iron uptake. Proc. Natl. Acad. Sci. USA 92, 2632–2636.

    Article  PubMed  CAS  Google Scholar 

  16. Hung I., Suzuki M., Yamaguchi Y., Yuan D., Klausner R., and Gitlin J. (1997). Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae. J. Biol. Chem. 272, 21,461–21,466.

    CAS  Google Scholar 

  17. Mercer J. F. (2001). The molecular basis of copper-transport diseases. Trends Mol. Med. 7, 64–69.

    Article  PubMed  CAS  Google Scholar 

  18. Kuper J., Llamas A., Hecht H. J., Mendel R. R., and Schwarz G. (2004). Structure of the molybdopterin-bound Cnx1G domain links molybdenum and copper metabolism. Nature 430, 803–806.

    Article  PubMed  CAS  Google Scholar 

  19. Harris Z. and Gitlin J. (1996). Genetic and molecular basis for copper toxicity. Am. J. Clin. Nutr. 63, 836S-841S.

    PubMed  CAS  Google Scholar 

  20. Klein D., Lichtmannegger J., Heinzmann U., and Summer K. H. (2000). Dissolution of copper-rich granules in hepatic lysosomes by D-penicillamine prevents the development of fulminant hepatitis in Long-Evans cinnamon rats. J. Hepatol. 32, 193–201.

    Article  PubMed  CAS  Google Scholar 

  21. Andersen J. K. (2004). Oxidative stress in neurodegeneration: cause or consequence? Nat. Med. 10, S18-S25.

    Article  PubMed  Google Scholar 

  22. Prohaska J. R. (2000). Long-term functional consequences of malnutrition during brain development: copper. Nutrition 16, 502–504.

    Article  PubMed  CAS  Google Scholar 

  23. Okeda R., Gei S., Chen I., Okaniwa M., Shinomiya M., and Matsubara O. (1991). Menkes' kinky hair disease: morphological and immunohistochemical comparison of two autopsied patients. Acta. Neuropathol. (Berl) 81, 450–457.

    Article  CAS  Google Scholar 

  24. Lutsenko S. and Petris M. J. (2003). Function and regulation of the mammalian copper-transporting ATPases: insights from biochemical and cell biological approaches. J. Membr. Biol. 191, 1–12.

    Article  PubMed  CAS  Google Scholar 

  25. Kumar N., Gross J. B., Jr., and Ahlskog J. E. (2004). Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 63, 33–39.

    PubMed  CAS  Google Scholar 

  26. Troost D., van Rossum A., Straks W., and Willemse J. (1982). Menkes' kinky hair disease. II. A clinicopathological report of three cases. Brain Dev. 4, 115–126.

    Article  PubMed  CAS  Google Scholar 

  27. Waggoner D., Bartnikas T., and Gitlin J. (1999). The role of copper in neurodegenerative disease. Neurobiol. Dis. 6, 221–230.

    Article  PubMed  CAS  Google Scholar 

  28. Gitlin J. D. (2003). Wilson disease. Gastroenterology 125, 1868–1877.

    Article  PubMed  Google Scholar 

  29. Hartter D. and Barnea A. (1988). Evidence for release of copper in the brain: depolarization-induced release of newly taken-up 67 copper. Synapse 2, 412–415.

    Article  PubMed  CAS  Google Scholar 

  30. Trombley P. Q., Horning M. S., and Blakemore L. J. (2000). Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. Biochemistry (Mosc) 65, 807–816.

    CAS  Google Scholar 

  31. Kardos J., Kovacs I., Hajos F., Kalman M., and 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.

    Article  PubMed  CAS  Google Scholar 

  32. Clements J. D., Lester R. A., Tong G., Jahr C. E., and Westbrook G. L. (1992). The time course of glutamate in the synaptic cleft. Science 258, 1498–1501.

    Article  PubMed  CAS  Google Scholar 

  33. Kozma M., Szerdahelyi P., and Kasa P. (1981). Histochemical detection of zinc and copper in various neurons of the central nervous system. Acta. Histochem. 69, 12–17.

    PubMed  CAS  Google Scholar 

  34. Sato M., Ohtomo K., Daimon T., Sugiyama T., and Iijima K. (1994). Localization of copper to afferent terminals in rat locus ceruleus, in contrast to mitochondrial copper in cerebellum. J. Histochem. Cytochem. 42, 1585–1591.

    PubMed  CAS  Google Scholar 

  35. Trombley P. and Shepherd G. (1996). Differential modulation by zinc and copper of amino acid receptors from rat olfactory bulb neurons. J. Neurophysiol. 76, 2536–2546.

    PubMed  CAS  Google Scholar 

  36. Vlachova V., Zemkova H. and Vyklicky L. J. (1996). Copper modulation of NMDA responses in mouse and rat cultured hippocampal neurons. Eur. J. Neurosci. 8, 2257–64.

    Article  PubMed  CAS  Google Scholar 

  37. Weiser T. and Wienrich M. (1996). The effects of copper ions on glutamate receptors in cultured rat cortical neurons. Brain Res. 742, 211–218.

    Article  PubMed  CAS  Google Scholar 

  38. Shen K. and Meyer T. (1999). Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science 284, 162–166.

    Article  PubMed  CAS  Google Scholar 

  39. Liao D., Scannevin R. H., and Huganir R. (2001). Activation of silent synapses by rapid activity-dependent synaptic recruitment of AMPA receptors. J. Neurosci. 21, 6008–6017.

    PubMed  CAS  Google Scholar 

  40. Lu W., Man H., Ju W., Trimble W., MacDonald J., and Wang Y. T. (2001). Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron. 29, 243–254.

    Article  PubMed  CAS  Google Scholar 

  41. Doreulee N., Yanovsky Y., and Haas H. L. (1997). Suppression of long-term potentiation in hippocampal slices by copper. Hippocampus 7, 666–669.

    Article  PubMed  CAS  Google Scholar 

  42. Leiva J. G. P. and Palestini M (2003). Copper interaction on the long-term potentiation. Arch. Ital. Biol. 141, 149–155.

    PubMed  CAS  Google Scholar 

  43. Horning M. S. and Trombley P. Q. (2001). Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms. J. Neurophysiol. 86, 1652–1660.

    PubMed  CAS  Google Scholar 

  44. Gruss M., Mathie A., Lieb W. R., and Franks N. P. (2004). The two-pore-domain K(+) channels TREK-1 and TASK-3 are differentially modulated by copper and zinc. Mol. Pharmacol. 66, 530–537.

    PubMed  CAS  Google Scholar 

  45. Franks N. P. and Honore E. (2004). The TREK K2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol. Sci. 25, 601–608.

    Article  PubMed  CAS  Google Scholar 

  46. Fu D., Beeler T. J., and Dunn T. M., (1995). Sequence, mapping and disruption of CCC2, a gene that cross-complements the Ca(2+)-sensitive phenotype of csg1 mutants and encodes a P-type ATPase belonging to the Cu(2+)-ATPase subfamily. Yeast 11, 283–292.

    Article  PubMed  CAS  Google Scholar 

  47. Schlief M. L., Craig A. M., and Gitlin J. D. (2005). IMDA receptor activation mediates copper homeostasis in hippocampal neurons. J. Neurosci. 25, 239–246.

    Article  PubMed  CAS  Google Scholar 

  48. Choi Y. B., Tenneti L., Le D. A., et al. (2000). Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nat. Neurosci. 3, 15–21.

    Article  PubMed  CAS  Google Scholar 

  49. Romeo A. A., Capobianco J. A., and English A. M. (2002). Heme nitrosylation of deoxyhemoglobin by s-nitrosoglutathione requires copper. J. Biol. Chem. 277, 24,135–24,141.

    Article  CAS  Google Scholar 

  50. Ding K., Mani K., Cheng F., Belting M., and Fransson L. A. (2002). Copper-dependent autocleavage of glypican-1 heparan sulfate by nitric oxide derived from intrinsic nitrosothiols. J. Biol. Chem. 277, 33,353–33,360.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Edward Mallickrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO

    Michelle L. Schlief & Jonathan D. Gitlin

Authors
  1. Michelle L. Schlief
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan D. Gitlin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan D. Gitlin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schlief, M.L., Gitlin, J.D. Copper homeostasis in the CNS. Mol Neurobiol 33, 81–90 (2006). https://doi.org/10.1385/MN:33:2:81

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:33:2:81

Index Entries

Search

Navigation