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.
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References
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.
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.
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.
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.
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.
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.
O'Halloran T. V. and Culotta V. C. (2000) Metallochaperones, an intracellular shuttle service for metal ions. J. Biol. Chem. 275, 25057–25060.
Rosenzweig A. C. (2001) Copper delivery by metallochaperone proteins. Acc. Chem. Res. 34, 119–128.
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.
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.
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.
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.
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.
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.
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.
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.
Mercer J. F. (2001). The molecular basis of copper-transport diseases. Trends Mol. Med. 7, 64–69.
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.
Harris Z. and Gitlin J. (1996). Genetic and molecular basis for copper toxicity. Am. J. Clin. Nutr. 63, 836S-841S.
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.
Andersen J. K. (2004). Oxidative stress in neurodegeneration: cause or consequence? Nat. Med. 10, S18-S25.
Prohaska J. R. (2000). Long-term functional consequences of malnutrition during brain development: copper. Nutrition 16, 502–504.
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.
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.
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.
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.
Waggoner D., Bartnikas T., and Gitlin J. (1999). The role of copper in neurodegenerative disease. Neurobiol. Dis. 6, 221–230.
Gitlin J. D. (2003). Wilson disease. Gastroenterology 125, 1868–1877.
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.
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.
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.
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.
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.
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.
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.
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.
Weiser T. and Wienrich M. (1996). The effects of copper ions on glutamate receptors in cultured rat cortical neurons. Brain Res. 742, 211–218.
Shen K. and Meyer T. (1999). Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science 284, 162–166.
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.
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.
Doreulee N., Yanovsky Y., and Haas H. L. (1997). Suppression of long-term potentiation in hippocampal slices by copper. Hippocampus 7, 666–669.
Leiva J. G. P. and Palestini M (2003). Copper interaction on the long-term potentiation. Arch. Ital. Biol. 141, 149–155.
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.
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.
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.
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.
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.
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.
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.
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.
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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
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DOI: https://doi.org/10.1385/MN:33:2:81