Key Points
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Long appreciated for its biological activity by the ancients, the zinc ion is now recognized as an important component of biological signalling cascades, with roles in practically every cell and tissue type. The role of zinc in central neuronal function and signalling is increasingly being appreciated. Of particular importance in both function and disease is the synaptic release of zinc from certain neurons by calcium-and impulse-dependent exocytosis. The neurons that release zinc in the mammalian cerebrum are all glutamatergic, and elaboration of the role that these neurons play in cerebral function is currently underway. The modulation of cortical excitability or 'tone' and the modulation of synaptic plasticity are two prominent theories.
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'Free' (rapidly exchangeable) Zn2+ is highly toxic. The 'safe' concentration of free zinc in the extracellular fluids of the brain is about 10 nM. Several proteins have been identified that modulate the uptake and export of zinc in all tissues, but only ZnT3 expression is unique to the brain, where it is confined to the synaptic vesicle membranes of a subset of glutamatergic fibres.
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Zinc has two clear roles in brain injury and brain disease. First, neurons increase their intracellular 'free' zinc by ∼1,000–10,000-fold after excitotoxic injury (such as stroke). Buffering that free zinc back down to normal levels can rescue affected neurons from apoptotic death. Second, Zn2+, in tandem with oxidative damage, induces the precipitation of amyloid-β into amyloid plaques and congophilic angiopathy, the pathological hallmarks of Alzheimer's disease. Genetic ablation of ZnT3 abolishes amyloid deposition in a transgenic model of Alzheimer's disease.
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Pharmacological therapies for excitotoxic brain injury and neurodegenerative brain disease based on the concept of buffering the free zinc in the brain (pZn) to the appropriate, physiological concentration (pZn ∼8) have been shown to be effective in preclinical models and are currently undergoing clinical trials. Some encouraging results have been obtained in both areas, with neuroprotection for stroke and slowed progression of symptoms in Alzheimer's disease.
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Zinc signalling is also attracting attention outside the brain, where many cell types also secrete zinc. Now that the appropriate tools and techniques for imaging, quantifying and administering zinc are becoming available, research in this field is set to accelerate.
Abstract
The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus1), and zinc has apparently been used fairly steadily throughout Roman2 and modern times (for example, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'.
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References
Arab, S. M. Medicine in Ancient Egypt [online], <http://www.arabworldbooks.com/articles8.htm> (2004).
Rehren, T. Small size, large scale Roman brass production in Germania Inferior. J. Archaeol. Sci. 26, 1083–1087 (1999).
Sandstead, H. H. Causes of iron and zinc deficiencies and their effects on brain. J. Nutr. 130, 347S–349S (2000).
Berg, J. M. Zinc fingers and other metal-binding domains. Elements for interactions between macromolecules. J. Biol. Chem. 265, 6513–6516 (1990).
Lock, K. & Janssen, C. R. Comparative toxicity of a zinc salt, zinc powder and zinc oxide to Eisenia fetida, Enchytraeus albidus and Folsomia candida. Chemosphere 53, 851–856 (2003).
Sensi, S. L., Yin, H. Z. & Weiss, J. H. AMPA/kainate receptor-triggered Zn2+ entry into cortical neurons induces mitochondrial Zn2+ uptake and persistent mitochondrial dysfunction. Eur. J. Neurosci. 12, 3813–3818 (2000).
Weiss, J. H., Sensi, S. L., & Koh, J. Y. Zn2+: a novel ionic mediator of neural injury in brain disease. Trends Pharmacol. Sci. 21, 395–401 (2000).
Sensi, S. L., Ton-That, D. & Weiss, J. H. Mitochondrial sequestration and Ca2+-dependent release of cytosolic Zn2+ loads in cortical neurons. Neurobiol. Dis. 10, 100–108 (2002).
Haase, H. & Maret, W. Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp. Cell Res. 291, 289–298 (2003).
Maret, W., Yetman, C. A. & Jiang, L. Enzyme regulation by reversible zinc inhibition: glycerol phosphate dehydrogenase as an example. Chem. Biol. Interact. 130–132, 891–901 (2001). Reveals the role of thionein as a zinc-shuttle that carries zinc signals to specific proteins.
Maret, W., Jacob, C., Vallee, B. L. & Fischer, E. H. Inhibitory sites in enzymes: zinc removal and reactivation by thionein. Proc. Natl Acad. Sci. USA 96, 1936–1940 (1999).
Choi, D. W. & Koh, J. Y. Zinc and brain injury. Annu. Rev. Neurosci. 21, 347–375 (1998).
Frederickson, C. J. Neurobiology of zinc and zinc-containing neurons. Int. Rev. Neurobiol. 31, 145–238 (1989).
Frederickson, C. J. & Bush, A. I. Synaptically released zinc: physiological functions and pathological effects. Biometals 14, 353–366 (2001).
Slomianka, L., Danscher, G. & Frederickson, C. J. Labeling of the neurons of origin of zinc-containing pathways by intraperitoneal injections of sodium selenite. Neuroscience 38, 843–854 (1990).
Maske, H. A new method for demonstrating A and B cells in the islands of Langerhans. (Translation) Klin. Wochenschr. 33, 1058 (1955).
Smart, T. G., Xie, X. & Krishek, B. J. Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc. Prog. Neurobiol. 42, 393–341 (1994).
Li, Y., Hough, C. J., Frederickson, C. J. & Sarvey, J. M. Induction of mossy fiber→Ca3 long-term potentiation requires translocation of synaptically released Zn2+. J. Neurosci. 21, 8015–8025 (2001). Shows that the translocation of zinc from presynaptic terminals into postsynaptic neurons has a role in physiological signalling — in LTP.
Brown, C. E. & Dyck, R. H. Rapid, experience-dependent changes in levels of synaptic zinc in primary somatosensory cortex of the adult mouse. J. Neurosci. 22, 2617–2625 (2002).
Garrett, B. & Slomianka, L. Postnatal development of zinc-containing cells and neuropil in the visual cortex of the mouse. Anat. Embryol. (Berl.) 186, 487–496 (1992).
Casanovas-Aguilar, C., Miro-Bernie, N. & Perez-Clausell, J. Zinc-rich neurones in the rat visual cortex give rise to two laminar segregated systems of connections. Neuroscience 110, 445–458 (2002).
Casanovas-Aguilar, C., Reblet, C., Perez-Clausell, J. & Bueno-Lopez, J. L. Zinc-rich afferents to the rat neocortex: projections to the visual cortex traced with intracerebral selenite injections. J. Chem. Neuroanat. 15, 97–109 (1998).
Casanovas-Aguilar, C. et al. Callosal neurones give rise to zinc-rich boutons in the rat visual cortex. Neuroreport 6, 497–500 (1995).
Frederickson, C. J. & Moncrieff, D. W. Zinc-containing neurons. Biol. Signals 3, 127–139 (1994).
Danscher, G., Howell, G., Perez-Clausell, J. & Hertel, N. The dithizone, Timm's sulphide silver and the selenium methods demonstrate a chelatable pool of zinc in CNS. A proton activation (PIXE) analysis of carbon tetrachloride extracts from rat brains and spinal cords intravitally treated with dithizone. Histochemistry 83, 419–422 (1985).
Frederickson, C. J., Rampy, B. A., Reamy-Rampy, S. & Howell, G. A. Distribution of histochemically reactive zinc in the forebrain of the rat. J. Chem. Neuroanat. 5, 521–530 (1992).
Sindreu, C. B., Varoqui, H., Erickson, J. D. & Perez-Clausell, J. Boutons containing vesicular zinc define a subpopulation of synapses with low AMPAR content in rat hippocampus. Cereb. Cortex 13, 823–829 (2003). Shows that almost half of synapses on some cortical dendrites are glutamate and zinc releasing, and that these are preferentially located at NMDA receptor-loaded spines.
Haug, F. M., Blackstad, T. W., Simonsen, A. H. & Zimmer, J. Timm's sulfide silver reaction for zinc during experimental anterograde degeneration of hippocampal mossy fibers. J. Comp. Neurol. 142, 23–31 (1971).
Sloviter, R. S. A selective loss of hippocampal mossy fiber Timm stain accompanies granule cell seizure activity induced by perforant path stimulation. Brain Res. 330, 150–153 (1985).
Frederickson, C. J., Hernandez, M. D., Goik, S. A., Morton, J. D. & McGinty, J. F. Loss of zinc staining from hippocampal mossy fibers during kainic acid induced seizures: a histofluorescence study. Brain Res. 446, 383–386 (1988).
Riba-Bosch, A. & Perez-Clausell, J. Response to kainic acid injections: changes in staining for zinc, FOS, cell death and glial response in the rat forebrain. Neuroscience 125, 803–818 (2004).
Sorensen, J. C., Mattsson, B., Andreasen, A. & Johansson, B. B. Rapid disappearance of zinc positive terminals in focal brain ischemia. Brain Res. 812, 265–269 (1998).
Suh, S. W. et al. Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Res. 852, 268–273 (2000).
Budde, T., Minta, A., White, J. A. & Kay, A. R. Imaging free zinc in synaptic terminals in live hippocampal slices. Neuroscience 79, 347–358 (1997).
Varea, E., Ponsoda, X., Molowny, A., Danscher, G. & Lopez-Garcia, C. Imaging synaptic zinc release in living nervous tissue. J. Neurosci. Methods 110, 57–63 (2001).
Perez-Clausell, J. & Danscher, G. Release of zinc sulphide accumulations into synaptic clefts after in vivo injection of sodium sulphide. Brain Res. 362, 358–361 (1986).
Quinta-Ferreira, M. E. & Matias, C. M. Hippocampal mossy fiber calcium transients are maintained during long-term potentiation and are inhibited by endogenous zinc. Brain Res. 1004, 52–60 (2004).
Assaf, S. Y. & Chung, S. H. Release of endogenous Zn2+ from brain tissue during activity. Nature 308, 734–736 (1984).
Howell, G. A., Welch, M. G. & Frederickson, C. J. Stimulation-induced uptake and release of zinc in hippocampal slices. Nature 308, 736–738 (1984). The discovery that zinc is released in a calcium- and impulse-dependent manner from central neurons.
Aniksztejn, L., Charton, G. & Ben Ari, Y. Selective release of endogenous zinc from the hippocampal mossy fibers in situ. Brain Res. 404, 58–64 (1987).
Charton, G., Rovira, C., Ben Ari, Y. & Leviel, V. Spontaneous and evoked release of endogenous Zn2+ in the hippocampal mossy fiber zone of the rat in situ. Exp. Brain Res. 58, 202–205 (1985).
Takeda, A., Sawashita, J., Takefuta, S., Ohnuma, M. & Okada, S. Role of zinc released by stimulation in rat amygdala. J. Neurosci. Res. 57, 405–410 (1999).
Zornow, M. et al. Zinc and glutamate signaling during ischemia and reperfusion. Neuroscience (in the press).
Thompson, R. B., Whetsell, W. O. Jr, Maliwal, B. P., Fierke, C. A. & Frederickson, C. J. Fluorescence microscopy of stimulated Zn(II) release from organotypic cultures of mammalian hippocampus using a carbonic anhydrase-based biosensor system. J. Neurosci. Methods 96, 35–45 (2000).
Li, Y., Hough, C. J., Suh, S. W., Sarvey, J. M. & Frederickson, C. J. Rapid translocation of Zn2+ from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J. Neurophysiol. 86, 2597–2604 (2001).
Ueno, S. et al. Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits. J. Cell Biol. 158, 215–220 (2002).
Altman, J., Brunner, R. L. & Bayer, S. A. The hippocampus and behavioral maturation. Behav. Biol. 8, 557–596 (1973).
Bayer, S. A. & Altman, J. Hippocampal development in the rat: cytogenesis and morphogenesis examined with autoradiography and low-level X-irradiation. J. Comp. Neurol. 158, 55–79 (1974).
Frederickson, C. J., Howell, G. A. & Frederickson, M. H. Zinc dithizonate staining in the cat hippocampus: relationship to the mossy-fiber neuropil and postnatal development. Exp. Neurol. 73, 812–823 (1981).
Kay, A. R. Evidence for chelatable zinc in the extracellular space of the hippocampus, but little evidence for synaptic release of Zn. J. Neurosci. 23, 6847–6855 (2003).
Sheline, C. T., Ying, H. S., Ling, C. S., Canzoniero, L. M. & Choi, D. W. Depolarization-induced 65zinc influx into cultured cortical neurons. Neurobiol. Dis. 10, 41–53 (2002).
Benters, J. et al. Study of the interactions of cadmium and zinc ions with cellular calcium homoeostasis using 19F-NMR spectroscopy. Biochem. J. 322, 793–799 (1997).
Marin, P., Israel, M., Glowinski, J. & Premont, J. Routes of zinc entry in mouse cortical neurons: role in zinc-induced neurotoxicity. Eur. J. Neurosci. 12, 8–18 (2000).
Thompson, R. B., Maliwal, B. P. & Zeng, H. H. Zinc biosensing with multiphoton excitation using carbonic anhydrase and improved fluorophores. J. Biomed. Opt. 5, 17–22 (2000).
Jia, Y., Jeng, J. M., Sensi, S. L. & Weiss, J. H. Zn2+ currents are mediated by calcium-permeable AMPA/kainate channels in cultured murine hippocampal neurones. J. Physiol. (Lond.) 543, 35–48 (2002).
Sensi, S. L. et al. Measurement of intracellular free zinc in living cortical neurons: routes of entry. J. Neurosci. 17, 9554–9564 (1997).
Atar, D., Backx, P. H., Appel, M. M., Gao, W. D. & Marban, E. Excitation-transcription coupling mediated by zinc influx through voltage-dependent calcium channels. J. Biol. Chem. 270, 2473–2477 (1995).
Kerchner, G. A., Canzoniero, L. M., Yu, S. P., Ling, C. & Choi, D. W. Zn2+ current is mediated by voltage-gated Ca2+ channels and enhanced by extracellular acidity in mouse cortical neurones. J. Physiol. (Lond.) 528, 39–52 (2000).
Yin, H. Z., Ha, D. H., Carriedo, S. G. & Weiss, J. H. Kainate-stimulated Zn2+ uptake labels cortical neurons with Ca2+-permeable AMPA/kainate channels. Brain Res. 781, 45–55 (1998).
Maret, W. The function of zinc metallothionein: a link between cellular zinc and redox state. J. Nutr. 130, 1455S–1458S (2000).
Maret, W. Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. Proc. Natl Acad. Sci. USA 91, 237–241 (1994).
Vallee, B. L. The function of metallothionein. Neurochem. Int. 27, 23–33 (1995).
Maret, W. & Vallee, B. L. Thiolate ligands in metallothioneins confer redox activity on zinc clusters. Proc. Natl Acad. Sci. USA 95, 3478–3482 (1998).
Maret, W. The function of zinc metallothionein: a link between cellular zinc and redox state. J. Nutr. 130 (5S Suppl.), 145S–148S (2000).
Jacob, C., Maret, W. & Vallee, B. L. Control of zinc transfer between thionein, metallothionein, and zinc proteins. Proc. Natl Acad. Sci. USA 95, 3489–3494 (1998).
Uchida, Y., Taiko, K., Titani, K. I. Y. & Tomonaga, M. The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 aminoacid metallothionein-like protein. Neuron 7, 337–347 (1991).
Palmiter, R. D., Findley, S. D., Whitmore, T. E. & Durnam, D. M. MT-III, a brain-specific member of the metallothionein gene family. Proc. Natl Acad. Sci. USA 89, 6333–6337 (1992).
Lee, J. Y., Kim, J. H., Palmiter, R. D. & Koh, J. Y. Zinc released from metallothionein-III may contribute to hippocampal CA1 and thalamic neuronal death following acute brain injury. Exp. Neurol. 184, 337–347 (2003).
Frederickson, C. J., Maret, W. & Cuajungco, M. P. Zinc and excitotoxic brain injury: a new model. Neuroscientist 10, 18–25 (2004).
Sensi, S. L., Yin, H. Z., Carriedo, S. G., Rao, S. S. & Weiss, J. H. Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc. Natl Acad. Sci. USA 96, 2414–2419 (1999).
Weiss, J. H. & Sensi, S. L. Ca2+-Zn2+ permeable AMPA or kainate receptors: possible key factors in selective neurodegeneration. Trends Neurosci. 23, 365–371 (2000).
Colvin, R. A., Davis, N., Nipper, R. W. & Carter, P. A. Zinc transport in the brain: routes of zinc influx and efflux in neurons. J. Nutr. 130, 1484S–1487S (2000).
Colvin, R. A., Davis, N., Nipper, R. W. & Carter, P. A. Evidence for a zinc/proton antiporter in rat brain. Neurochem. Int. 36, 539–547 (2000).
Wei, G., Hough, C. J., Li, Y. & Sarvey, J. M. Characterization of extracellular accumulation of Zn2+ during ischemia and reperfusion of hippocampus slices in rat. Neuroscience 125, 867–877 (2004).
Frederickson, C. J., Maret, W. & Cuajungco, M. P. Zinc and excitotoxic brain injury: a new model. Neuroscientist 10, 18–25 (2004).
Bossy-Wetzel, E. et al. Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron 41, 351–365 (2004).
Aizenman, E. et al. Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release. J. Neurochem. 75, 1878–1888 (2000). Introduces the notion of thiol-liberated free zinc as a generic apoptosis death signal.
Rameau, G. A., Chiu, L. Y. & Ziff, E. B. NMDA receptor regulation of nNOS phosphorylation and induction of neuron death. Neurobiol. Aging 24, 1123–1133 (2003).
Rameau, G. A., Chiu, L. Y. & Ziff, E. B. Bidirectional regulation of neuronal nitric-oxide synthase phosphorylation at serine 847 by the N-methyl-D-aspartate receptor. J. Biol. Chem. 279, 14307–14314 (2004).
Colvin, R. A., Fontaine, C. P., Laskowski, M. & Thomas, D. Zn2+ transporters and Zn2+ homeostasis in neurons. Eur. J. Pharmacol. 479, 171–185 (2003).
Palmiter, R. D., Cole, T. B., Quaife, C. J. & Findley, S. D. ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc. Natl Acad. Sci. USA 93, 14934–14939 (1996). The first evidence to indicate that the ZnT3 protein is necessary for zinc accumulation in neuronal vesicles.
Segal, D. et al. A role for ZnT-1 in regulating cellular cation influx. Biochem. Biophys. Res. Commun. 323, 1145–1150 (2004).
Thompson, R., Frederickson, C., Fierke, C. & Bector, G. in Practical Aspects of Fluorescence Sensing in Biology. (ed. Thompson, R.) (CRC, Florida, in the press).
Paoletti, P., Ascher, P. & Neyton, J. High-affinity zinc inhibition of NMDA NR1–NR2A receptors. J. Neurosci. 17, 5711–5725 (1997).
Patton, C., Thompson, S. & Epel, D. Some precautions in using chelators to buffer metals in biological solutions. Cell Calcium 35, 427–431 (2004).
Aslamkhan, A. G., Aslamkhan, A. & Ahearn, G. A. Preparation of metal ion buffers for biological experimentation: a methods approach with emphasis on iron and zinc. J. Exp. Zool. 292, 507–522 (2002).
Thompson, R. B. et al. Fluorescent zinc indicators for neurobiology. J. Neurosci. Methods 118, 63–75 (2002).
Peters, S., Koh, J. & Choi, D. W. Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons. Science 236, 589–593 (1987).
Low, C. M., Zheng, F., Lyuboslavsky, P. & Traynelis, S. F. Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors. Proc. Natl Acad. Sci. USA 97, 11062–11067 (2000).
Coughenour, L. L. & Barr, B. M. Use of trifluoroperazine isolates a [3H]ifenprodil binding site in rat brain membranes with the pharmacology of the voltage-independent ifenprodil site on N-methyl-D-aspartate receptors containing NR2B subunits. J. Pharmacol. Exp. Ther. 296, 150–159 (2001).
Martin, D., Ault, B. & Nadler, J. V. NMDA receptor-mediated depolarizing action of proline on CA1 pyramidal cells. Eur. J. Pharmacol. 219, 59–66 (1992).
Vogt, K., Mellor, J., Tong, G. & Nicoll, R. The actions of synaptically released zinc at hippocampal mossy fiber synapses. Neuron 26, 187–196 (2000).
Mitchell, C. L. & Barnes, M. I. Proconvulsant action of diethyldithiocarbamate in stimulation of the perforant path. Neurotoxicol. Teratol. 15, 165–171 (1993).
Mitchell, C. L., Barnes, M. I. & Grimes, L. M. Diethyldithiocarbamate and dithizone augment the toxicity of kainic acid. Brain Res. 506, 327–330 (1990).
Dominguez, M. I., Blasco-Ibanez, J. M., Crespo, C., Marques-Mari, A. I. & Martinez-Guijarro, F. J. Calretinin/PSA-NCAM immunoreactive granule cells after hippocampal damage produced by kainic acid and DEDTC treatment in mouse. Brain Res. 966, 206–217 (2003).
Dominguez, M. I., Blasco-Ibanez, J. M., Crespo, C., Marques-Mari, A. I. & Martinez-Guijarro, F. J. Zinc chelation during non-lesioning overexcitation results in neuronal death in the mouse hippocampus. Neuroscience 116, 791–806 (2003).
Lin, D. D., Cohen, A. S. & Coulter, D. A. Zinc-induced augmentation of excitatory synaptic currents and glutamate receptor responses in hippocampal CA3 neurons. J. Neurophysiol. 85, 1185–1196 (2001).
Manzerra, P. et al. Zinc induces a Src family kinase-mediated up-regulation of NMDA receptor activity and excitotoxicity. Proc. Natl Acad. Sci. USA 98, 11055–11061 (2001).
Kim, T. Y., Hwang, J. J., Yun, S. H., Jung, M. W. & Koh, J. Y. Augmentation by zinc of NMDA receptor-mediated synaptic responses in CA1 of rat hippocampal slices: mediation by Src family tyrosine kinases. Synapse 46, 49–56 (2002).
Westbrook, G. L. & Mayer, M. L. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature 328, 640–643 (1987).
Smart, T. G. & Constanti, A. Pre- and postsynaptic effects of zinc on in vitro prepyriform neurones. Neurosci. Lett. 40, 205–211 (1983).
Horning, M. S. & Trombley, P. Q. Zinc and copper influence excitability of rat olfactory bulb neurons by multiple mechanisms. J. Neurophysiol. 86, 1652–1660 (2001).
Legendre, P. & Westbrook, G. L. Noncompetitive inhibition of γ-aminobutyric acidA channels by Zn. Mol. Pharmacol. 39, 267–274 (1991).
Ben Ari, Y. & Cherubini, E. Zinc and GABA in developing brain. Nature 353, 220 (1991).
Hosie, A. M., Dunne, E. L., Harvey, R. J. & Smart, T. G. Zinc-mediated inhibition of GABAA receptors: discrete binding sites underlie subtype specificity. Nature Neurosci. 6, 362–369 (2003).
Xie, X. M. & Smart, T. G. A physiological role for endogenous zinc in rat hippocampal synaptic neurotransmission. Nature 349, 521–524 (1991).
Ruiz, A., Walker, M. C., Fabian-Fine, R. & Kullmann, D. M. Endogenous zinc inhibits GABAA receptors in a hippocampal pathway. J. Neurophysiol. 91, 1091–1096 (2004).
Xie, X., Hider, R. C. & Smart, T. G. Modulation of GABA-mediated synaptic transmission by endogenous zinc in the immature rat hippocampus in vitro. J. Physiol. (Lond.) 478, 75–86 (1994).
Wang, Z., Li, J. Y., Dahlstrom, A. & Danscher, G. Zinc-enriched GABAergic terminals in mouse spinal cord. Brain Res. 921, 165–172 (2001).
Buhl, E. H., Otis, T. S. & Mody, I. Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model. Science 271, 369–373 (1996).
Coulter, D. A. Epilepsy-associated plasticity in γ-aminobutyric acid receptor expression, function, and inhibitory synaptic properties. Int. Rev. Neurobiol. 45, 237–252 (2001).
Shumate, M. D., Lin, D. D., Gibbs, J. W., Holloway, K. L. & Coulter, D. A. GABAA receptor function in epileptic human dentate granule cells: comparison to epileptic and control rat. Epilepsy Res. 32, 114–128 (1998).
Molnar, P. & Nadler, J. V. Lack of effect of mossy fiber-released zinc on granule cell GABAA receptors in the pilocarpine model of epilepsy. J. Neurophysiol. 85, 1932–1940 (2001).
Kapur, J. & MacDonald, R. L. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J. Neurosci. 17, 7532–7540 (1997).
Brooks-Kayal, A. R. et al. γ-Aminobutyric acidA receptor subunit expression predicts functional changes in hippocampal dentate granule cells during postnatal development. J. Neurochem. 77, 1266–1278 (2001).
Kretschmannova, K., Svobodova, I. & Zemkova, H. Day-night variations in zinc sensitivity of GABAA receptor-channels in rat suprachiasmatic nucleus. Brain Res. Mol. Brain Res. 120, 46–51 (2003).
Schetz, J. A., Chu, A. & Sibley, D. R. Zinc modulates antagonist interactions with D2-like dopamine receptors through distinct molecular mechanisms. J. Pharmacol. Exp. Ther. 289, 956–964 (1999).
Schetz, J. A. & Sibley, D. R. Zinc allosterically modulates antagonist binding to cloned D1 and D2 dopamine receptors. J. Neurochem. 68, 1990–1997 (1997).
Uki, M. & Narahashi, T. Modulation of serotonin-induced currents by metals in mouse neuroblastoma cells. Arch. Toxicol. 70, 652–660 (1996).
Swaminath, G., Steenhuis, J., Kobilka, B. & Lee, T. W. Allosteric modulation of β2-adrenergic receptor by Zn2+. Mol. Pharmacol. 61, 65–72 (2002).
Rosati, A. M. & Traversa, U. Mechanisms of inhibitory effects of zinc and cadmium ions on agonist binding to adenosine A1 receptors in rat brain. Biochem. Pharmacol. 58, 623–632 (1999).
Traversa, U. & Rosati, A. Zinc and cadmium ions differently modulate A1 adenosine receptors. Acta Physiol. Hung. 84, 465–467 (1996).
Palma, E., Maggi, L., Miledi, R. & Eusebi, F. Effects of Zn2+ on wild and mutant neuronal α7 nicotinic receptors. Proc. Natl Acad. Sci. USA 95, 10246–10250 (1998).
Garcia-Colunga, J., Gonzalez-Herrera, M. & Miledi, R. Modulation of α2β4 neuronal nicotinic acetylcholine receptors by zinc. Neuroreport 12, 147–150 (2001).
Chattipakorn, S. C. & McMahon, L. L. Pharmacological characterization of glycine-gated chloride currents recorded in rat hippocampal slices. J. Neurophysiol. 87, 1515–1525 (2002).
Baron, A., Schaefer, L., Lingueglia, E., Champigny, G. & Lazdunski, M. Zn2+ and H+ are coactivators of acid-sensing ion channels. J. Biol. Chem. 276, 35361–35367 (2001).
Baron, A., Waldmann, R. & Lazdunski, M. ASIC-like, proton-activated currents in rat hippocampal neurons. J. Physiol. (Lond.) 539, 485–494 (2002).
Birinyi, A., Parker, D., Antal, M. & Shupliakov, O. Zinc co-localizes with GABA and glycine in synapses in the lamprey spinal cord. J. Comp. Neurol. 433, 208–221 (2001).
Laube, B. et al. Modulation by zinc ions of native rat and recombinant human inhibitory glycine receptors. J. Physiol. (Lond.) 483, 613–619 (1995).
Quest, A. F., Bloomenthal, J., Bardes, E. S. & Bell, R. M. The regulatory domain of protein kinase C coordinates four atoms of zinc. J. Biol. Chem. 267, 10193–10197 (1992).
Bloomenthal, A. B., Goldwater, E., Pritchett, D. B. & Harrison, N. L. Biphasic modulation of the strychnine-sensitive glycine receptor by Zn2+. Mol. Pharmacol. 46, 1156–1159 (1994).
Choi, D. W. Zinc neurotoxicity may contribute to selective neuronal death following transient global cerebral ischemia. Cold Spring Harb. Symp. Quant. Biol. 61, 385–387 (1996).
Choi, D. W. Possible mechanisms limiting N-methyl-D-aspartate receptor overactivation and the therapeutic efficacy of N-methyl-D-aspartate antagonists. Stroke 21, III20–III22 (1990).
Hershfinkel, M., Moran, A., Grossman, N. & Sekler, I. A zinc-sensing receptor triggers the release of intracellular Ca2+ and regulates ion transport. Proc. Natl Acad. Sci. USA 98, 11749–11754 (2001).
Vandenberg, R. J., Mitrovic, A. D. & Johnston, G. A. Molecular basis for differential inhibition of glutamate transporter subtypes by zinc ions. Mol. Pharmacol. 54, 189–196 (1998).
Richfield, E. K. Zinc modulation of drug binding, cocaine affinity states, and dopamine uptake on the dopamine uptake complex. Mol. Pharmacol. 43, 100–108 (1993).
Itoh, M. & Ebadi, M. The selective inhibition of hippocampal glutamic acid decarboxylase in zinc-induced epileptic seizures. Neurochem. Res. 7, 1287–1298 (1982).
Morton, J. D., Howell, G. A. & Frederickson, C. J. Effects of subcutaneous injections of zinc chloride on seizures induced by noise and by kainic acid. Epilepsia 31, 139–144 (1990).
Xie, X. & Smart, T. G. Modulation of long-term potentiation in rat hippocampal pyramidal neurons by zinc. Pflugers Arch. 427, 481–486 (1994).
Weiss, J. H., Koh, J. Y., Christine, C. W. & Choi, D. W. Zinc and LTP. Nature 338, 212 (1989).
Vincent, S. R. & Semba, K. A heavy metal marker of the developing striatal mosaic. Brain Res. Dev. Brain Res. 45, 155–159 (1989).
Land, P. W. & Shamalla-Hannah, L. Transient expression of synaptic zinc during development of uncrossed retinogeniculate projections. J. Comp. Neurol. 433, 515–525 (2001).
Dyck, R., Beaulieu, C. & Cynader, M. Histochemical localization of synaptic zinc in the developing cat visual cortex. J. Comp. Neurol. 329, 53–67 (1993).
Lu, Y. M. et al. Endogenous Zn2+ is required for the induction of long-term potentiation at rat hippocampal mossy fiber-CA3 synapses. Synapse 38, 187–197 (2000).
Murphy, J. V. Intoxication following ingestion of elemental zinc. JAMA 212, 2119–2120 (1970).
Yokoyama, M., Koh, J. & Choi, D. W. Brief exposure to zinc is toxic to cortical neurons. Neurosci. Lett. 71, 351–355 (1986).
Frederickson, C. J., Klitenick, M. A., Manton, W. I. & Kirkpatrick, J. B. Cytoarchitectonic distribution of zinc in the hippocampus of man and the rat. Brain Res. 273, 335–339 (1983).
Siesjo, B. K. Basic mechanisms of traumatic brain damage. Ann. Emerg. Med. 22, 959–969 (1993).
Hossmann, K. A. Periinfarct depolarizations. Cerebrovasc. Brain Metab. Rev. 8, 195–208 (1996).
Weiss, J. H., Hartley, D. M., Koh, J. Y. & Choi, D. W. AMPA receptor activation potentiates zinc neurotoxicity. Neuron 10, 43–49 (1993).
Koh, J. Y. & Choi, D. W. Zinc toxicity on cultured cortical neurons: involvement of N-methyl-D-aspartate receptors. Neuroscience 60, 1049–1057 (1994).
Kolenko, V. M. et al. Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes. Apoptosis 6, 419–429 (2001).
Canzoniero, L. M., Turetsky, D. M. & Choi, D. W. Measurement of intracellular free zinc concentrations accompanying zinc-induced neuronal death. J. Neurosci. 19, RC31 (1999).
Frederickson, C. J., Hernandez, M. D. & McGinty, J. F. Translocation of zinc may contribute to seizure-induced death of neurons. Brain Res. 480, 317–321 (1989). The discovery that zinc accumulates in neurons injured by excitotoxicity.
Tonder, N., Johansen, F. F., Frederickson, C. J., Zimmer, J. & Diemer, N. H. Possible role of zinc in the selective degeneration of dentate hilar neurons after cerebral ischemia in the adult rat. Neurosci. Lett. 109, 247–252 (1990).
Koh, J. Y. et al. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272, 1013–1016 (1996). The first demonstation that chelation of metals can rescue neurons from ischaemic injury and death.
Lee, J. M. et al. Zinc translocation accelerates infarction after mild transient focal ischemia. Neuroscience 115, 871–878 (2002).
Yin, H. Z., Sensi, S. L., Ogoshi, F. & Weiss, J. H. Blockade of Ca2+-permeable AMPA/kainate channels decreases oxygen-glucose deprivation-induced Zn2+ accumulation and neuronal loss in hippocampal pyramid neurons. J. Neurosci. 22, 1273–1279 (2002).
Suh, S. W., Garnier, P., Aoyama, K., Chen, Y. & Swanson, R. A. Zinc release contributes to hypoglycemia-induced neuronal death. Neurobiol. Dis. 16, 538–545 (2004).
Lee, J. Y., Cole, T. B., Palmiter, R. D. & Koh, J. Y. Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null mice after seizures: evidence against synaptic vesicle origin. J. Neurosci. 20, RC79 (2000). The first study to show that zinc accumulation in injured neurons is independent of synpatic vesicle zinc.
Frederickson, C. J. et al. Depletion of intracellular zinc from neurons by use of an extracellular chelator in vivo and in vitro. J. Histochem. Cytochem. 50, 1659–1662 (2002).
Sunderman, F. W. Jr. The influence of zinc on apoptosis. Ann. Clin. Lab. Sci. 25, 134–142 (1995).
Kim, E. Y. et al. Zn2+ entry produces oxidative neuronal necrosis in cortical cell cultures. Eur. J. Neurosci. 11, 327–334 (1999).
Sensi, S. L., Yin, H. Z. & Weiss, J. H. Glutamate triggers preferential Zn2+ flux through Ca2+ permeable AMPA channels and consequent ROS production. Neuroreport 10, 1723–1727 (1999). Showed that calcium permeable AMPA/Kainate channels are the main route of zinc entry to postsynaptic neurons. Also links zinc and oxidative stress.
Noh, K. M., Kim, Y. H. & Koh, J. Y. Mediation by membrane protein kinase C of zinc-induced oxidative neuronal injury in mouse cortical cultures. J. Neurochem. 72, 1609–1616 (1999).
Kim, Y. H., Kim, E. Y., Gwag, B. J., Sohn, S. & Koh, J. Y. Zinc-induced cortical neuronal death with features of apoptosis and necrosis: mediation by free radicals. Neuroscience 89, 175–182 (1999).
Seo, S. R. et al. Zn2+-induced ERK activation mediated by reactive oxygen species cause cell death in differentiated PC12 cells. J. Neurochem. 78, 600–610 (2001).
Noh, K. M. & Koh, J. Y. Induction and activation by zinc of NADPH oxidase in cultured cortical neurons and astrocytes. J. Neurosci. 20, RC111 (2000). NADPH oxidase might be one of the effectors of zinc-induced oxidative stress.
Lobner, D. et al. Zinc-induced neuronal death in cortical neurons. Cell Mol. Biol. (Noisy-le-grand) 46, 797–806 (2000).
Park, J. A., Lee, J. Y., Sato, T. A. & Koh, J. Y. Co-induction of p75NTR and p75NTR-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat. J. Neurosci. 20, 9096–9103 (2000).
Mukai, J. et al. NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR. J. Biol. Chem. 275, 17566–17570 (2000).
Jiang, D., Sullivan, P. G., Sensi, S. L., Steward, O. & Weiss, J. H. Zn2+ induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria. J. Biol. Chem. 276, 47524–47529 (2001).
Yi, J. S., Lee, S. K., Sato, T. A. & Koh, J. Y. Co-induction of p75NTRand the associated death executor NADE in degenerating hippocampal neurons after kainate-induced seizures in the rat. Neurosci. Lett. 347, 126–130 (2003).
Yang, Y., Maret, W. & Vallee, B. L. Differential fluorescence labeling of cysteinyl clusters uncovers high tissue levels of thionein. Proc. Natl Acad. Sci. USA 98, 5556–5559 (2001).
Frederickson, C. J., Cuajungco, M. P., LaBuda, C. J. & Suh, S. W. Nitric oxide causes apparent release of zinc from presynaptic boutons. Neuroscience 115, 471–474 (2002).
Kim, Y. H. & Koh, J. Y. 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. 177, 407–418 (2002).
Ha, H. C. & Snyder, S. H. Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc. Natl Acad. Sci. USA 96, 13978–13982 (1999).
Szabo, C. & Dawson, V. L. Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol. Sci. 19, 287–298 (1998).
Sheline, C. T., Wang, H., Cai, A. -L., Dawson, V. L. & Choi, D. W. Involvement of poly ADP ribosyl polymerase-1 in acute but not chronic zinc toxicity. Eur. J. Neurosci. 18, 1402–1409 (2003).
Terry, R. D. & Katzman, R. Senile dementia of the Alzheimer type. Ann. Neurol. 14, 497–506 (1983).
Glenner, G. G. & Wong, C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).
Masters, C. L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci. USA 82, 4245–4249 (1985).
Bush, A. I., Pettingell, W. H. Jr, Paradis, M. D. & Tanzi, R. E. Modulation of A β adhesiveness and secretase site cleavage by zinc. J. Biol. Chem. 269, 12152–12158 (1994).
Bush, A. I. et al. Rapid induction of Alzheimer A β amyloid formation by zinc. Science 265, 1464–1467 (1994). First report that amyloid-β specifically and saturably binds and is precipitated by zinc.
Regland, B. et al. Treatment of Alzheimer's disease with clioquinol. Dement. Geriatr. Cogn. Disord. 12, 408–414 (2001).
Ritchie, C. W. et al. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch. Neurol. 60, 1685–1691 (2003).
Bush, A. I., Pettingell, W. H. Jr. de Paradis, M., Tanzi, R. E. & Wasco, W. The amyloid β-protein precursor and its mammalian homologues. Evidence for a zinc-modulated heparin-binding superfamily. J. Biol. Chem. 269, 26618–26621 (1994).
Bush, A. I. et al. A novel zinc(II) binding site modulates the function of the β A4 amyloid protein precursor of Alzheimer's disease. J. Biol. Chem. 268, 16109–16112 (1993).
Multhaup, G., Bush, A. I., Pollwein, P. & Masters, C. L. Interaction between the zinc (II) and the heparin binding site of the Alzheimer's disease β A4 amyloid precursor protein (APP). FEBS Lett. 355, 151–154 (1994).
Multhaup, G. et al. Copper-binding amyloid precursor protein undergoes a site-specific fragmentation in the reduction of hydrogen peroxide. Biochemistry 37, 7224–7230 (1998).
Liu, S. T., Howlett, G. & Barrow, C. J. Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A β peptide of Alzheimer's disease. Biochemistry 38, 9373–9378 (1999).
Esch, F. S. et al. Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248, 1122–1124 (1990).
Huang, X. et al. Zinc-induced Alzheimer's Aβ1-40 aggregation is mediated by conformational factors. J. Biol. Chem. 272, 26464–26470 (1997).
Atwood, C. S. et al. Dramatic aggregation of Alzheimer Aβ by Cu(II) is induced by conditions representing physiological acidosis. J. Biol. Chem. 273, 12817–12826 (1998).
Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L. & Markesbery, W. R. Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci. 158, 47–52 (1998).
Opazo, C. et al. Metalloenzyme-like activity of Alzheimer's disease β-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2 . J. Biol. Chem. 277, 40302–40308 (2002).
Dong, J. et al. Metal binding and oxidation of amyloid-β within isolated senile plaque cores: Raman microscopic evidence. Biochemistry 42, 2768–2773 (2003).
Atwood, C. S. et al. Characterization of copper interactions with Alzheimer amyloid β peptides: identification of an attomolar-affinity copper binding site on amyloid β1-42. J. Neurochem. 75, 1219–1233 (2000).
White, A. R. et al. The Alzheimer's disease amyloid precursor protein modulates copper-induced toxicity and oxidative stress in primary neuronal cultures. J. Neurosci. 19, 9170–9179 (1999).
Smith, M. A. et al. Amyloid-β deposition in Alzheimer transgenic mice is associated with oxidative stress. J. Neurochem. 70, 2212–2215 (1998).
Cuajungco, M. P., Frederickson, C. J. & Bush, A. I. Amyloid-β metal interaction and metal chelation. Subcell. Biochem. 38, 235–254 (2005).
Bellingham, S. A. et al. Gene knockout of amyloid precursor protein and amyloid precursor-like protein-2 increases cellular copper levels in primary mouse cortical neurons and embryonic fibroblasts. J. Neurochem. 91, 423–428 (2004).
Maynard, C. J. et al. Overexpression of Alzheimer's disease amyloid-β opposes the age-dependent elevations of brain copper and iron. J. Biol. Chem. 277, 44670–44676 (2002).
Bush, A. I. The metallobiology of Alzheimer's disease. Trends Neurosci. 26, 207–214 (2003).
Huang, X. et al. Cu(II) potentiation of Alzheimer Aβ neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J. Biol. Chem. 274, 37111–37116 (1999). Genetic ablation of ZnT3 decreases vessel wall amyloid-β deposition in an APP transgenic mouse model of Alzheimer's disease.
Huang, X. et al. The A β peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38, 7609–7616 (1999).
Rottkamp, C. A. et al. Redox-active iron mediates amyloid-β toxicity. Free Radic. Biol. Med. 30, 447–450 (2001).
Atwood, C. S. et al. Copper catalyzed oxidation of Alzheimer Aβ. Cell Mol. Biol. (Noisy-le-grand) 46, 777–783 (2000).
Atwood, C. S. et al. Copper mediates dityrosine cross-linking of Alzheimer's amyloid-β. Biochemistry 43, 560–568 (2004).
Barnham, K. J. et al. Neurotoxic, redox-competent Alzheimer's β-amyloid is released from lipid membrane by methionine oxidation. J. Biol. Chem. 278, 42959–42965 (2003).
McLean, C. A. et al. Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860–866 (1999).
Cherny, R. A. et al. Aqueous dissolution of Alzheimer's disease Aβ amyloid deposits by biometal depletion. J. Biol. Chem. 274, 23223–23228 (1999). Amyloid-β causes toxicity by producing hydrogen peroxide catalytically on binding copper ions.
Head, E. et al. Oxidation of Aβ and plaque biogenesis in Alzheimer's disease and Down syndrome. Neurobiol. Dis. 8, 792–806 (2001).
Turnbull, S., Tabner, B. J., El Agnaf, O. M., Twyman, L. J. & Allsop, D. New evidence that the Alzheimer β-amyloid peptide does not spontaneously form free radicals: an ESR study using a series of spin-traps. Free Radic. Biol. Med. 30, 1154–1162 (2001).
Hensley, K. et al. Brain regional correspondence between Alzheimer's disease histopathology and biomarkers of protein oxidation. J. Neurochem. 65, 2146–2156 (1995).
Lee, J. Y., Cole, T. B., Palmiter, R. D., Suh, S. W. & Koh, J. Y. Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc. Natl Acad. Sci. USA 99, 7705–7710 (2002).
Friedlich, A. L. et al. Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease. J. Neurosci. 24, 3453–3459 (2004). The precipitation of amyloid-β in the post-mortem brain tissue of patients with Alzheimer's disease is reversible with zinc chelation.
Sillevis Smitt, P. A. et al. Metallothionein in amyotrophic lateral sclerosis. Biol. Signals 3, 193–197 (1994).
Sillevis Smitt, P. A., Blaauwgeers, H. G., Troost, D. & de Jong, J. M. Metallothionein immunoreactivity is increased in the spinal cord of patients with amyotrophic lateral sclerosis. Neurosci. Lett. 144, 107–110 (1992).
Reaume, A. G. et al. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nature Genet. 13, 43–47 (1996).
Liochev, S. I., Chen, L. L., Hallewell, R. A. & Fridovich, I. Superoxide-dependent peroxidase activity of H48Q: a superoxide dismutase variant associated with familial amyotrophic lateral sclerosis. Arch. Biochem. Biophys. 346, 263–268 (1997).
Singh, R. J. et al. Reexamination of the mechanism of hydroxyl radical adducts formed from the reaction between familial amyotrophic lateral sclerosis-associated Cu,Zn superoxide dismutase mutants and H2O2 . Proc. Natl Acad. Sci. USA 95, 6675–6680 (1998).
Roe, J. A. et al. In vivo peroxidative activity of FALS-mutant human CuZnSODs expressed in yeast. Free Radic. Biol. Med. 32, 169–174 (2002).
Estevez, A. G. et al. Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science 286, 2498–2500 (1999).
Gong, Y. H. & Elliott, J. L. Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis. Exp. Neurol. 162, 27–36 (2000).
Nagano, S. et al. Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner. Eur. J. Neurosci. 13, 1363–1370 (2001).
Puttaparthi, K. et al. Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins. J. Neurosci. 22, 8790–8796 (2002).
Canzoniero, L. M., Manzerra, P., Sheline, C. T. & Choi, D. W. Membrane-permeant chelators can attenuate Zn2+-induced cortical neuronal death. Neuropharmacology 45, 420–428 (2003).
Lee, J. Y., Friedman, J. E., Angel, I., Kozak, A. & Koh, J. Y. The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human β-amyloid precursor protein transgenic mice. Neurobiol. Aging 25, 1315–1321 (2004).
Rosenberg, G., Angel, I., Kozak, A., Rehovot, I. & Schneider, D. Evaluation of safety and changes in the NIH stroke scale, Rankin, and Barthel scores following DP-b99 administration in acute stroke patients. Stroke 35, 338 (2004).
Kawahara, M., Kato-Negishi, M. & Kuroda, Y. Pyruvate blocks zinc-induced neurotoxicity in immortalized hypothalamic neurons. Cell. Mol. Neurobiol. 22, 87–93 (2002).
Kelland, E. E., Kelly, M. D. & Toms, N. J. Pyruvate limits zinc-induced rat oligodendrocyte progenitor cell death. Eur. J. Neurosci. 19, 287–294 (2004).
Lee, J. Y., Kim, Y. H. & Koh, J. Y. Protection by pyruvate against transient forebrain ischemia in rats. J. Neurosci. 21, RC171 (2001).
Dobsak, P. & Courderot-Masuyer, C. Antioxidative properties of pyruvate and protection of the ischemic rat heart during cardioplegia. J. Cardiovasc. Pharmacol. 34, 651–659 (1999).
Sheline, C. T., Behrens, M. M. & Choi, D. W. Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD+ and inhibition of glycolysis. J. Neurosci. 20, 3139–3146 (2000).
Albers, G. W. Advances in intravenous thrombolytic therapy for treatment of acute stroke. Neurology 57, S77–S81 (2001).
Tsirka, S. E., Rogove, A. D. & Strickland, S. Neuronal cell death and tPA63. Nature 384, 123–124 (1996).
Kim, Y. H., Park, J. H., Hong, S. H. & Koh, J. Y. Nonproteolytic neuroprotection by human recombinant tissue plasminogen activator. Science 284, 647–650 (1999).
Siddiq, M. M. & Tsirka, S. E. Modulation of zinc toxicity by tissue plasminogen activator. Mol. Cell. Neurosci. 25, 162–171 (2004).
Bennett, M. R. The concept of transmitter receptors: 100 years on. Neuropharmacology 39, 523–546 (2000).
Fatt, P. & Katz, B. The effect of inhibitory nerve impulses on a crustacean muscle fibre. J. Physiol. (Lond.) 121, 374–389 (1953).
Whitcomb, D. C. & Taylor, I. L. A new twist in the brain-gut axis. Am. J. Med. Sci. 304, 334–338 (1992).
Delezenne, C. & Morel, H. Action catalytique des venins des serpents sur les acids nucleiques. Cr. Acad. Sci. 244–246 (1919).
Frederickson, C. J., Perez-Clausell, J. & Danscher, G. Zinc-containing 7S-NGF complex. Evidence from zinc histochemistry for localization in salivary secretory granules. J. Histochem. Cytochem. 35, 579–583 (1987).
Kristiansen, L. H., Rungby, J., Sondergaard, L. G., Stoltenberg, M. & Danscher, G. Autometallography allows ultrastructural monitoring of zinc in the endocrine pancreas. Histochem. Cell Biol. 115, 125–129 (2001).
Sorensen, M. B., Stoltenberg, M., Juhl, S., Danscher, G. & Ernst, E. Ultrastructural localization of zinc ions in the rat prostate: an autometallographic study. Prostate 31, 125–130 (1997).
Muller, A. & Geyer, G. Submicroscopic heavy metal localization in the prosecreta of the Paneth cells of the mouse. (Translation) Gegenbaurs. Morphol. Jahrb. 113, 70–77 (1969).
Gustafson, G. T. Heavy metals in rat mast cell granules. Lab. Invest. 17, 588–598 (1967).
Gol'dberg, E. D., Bovt, V. D. & Eshchenko, V. A. Diagnostic value of selective cytochemical reaction to zinc in peripheral blood granulocytes. (Translation) Klin. Lab Diagn. 25–27 (1993).
Ieshchenko, V. A., Bovt, V. D., Skoliboh, S. O. & Volovyk, M. V. The cytochemical dithizone reaction of the blood granulocytes in zinc-deficient states. (Translation). Lik. Sprava. 86–88 (1994).
Thorlacius-Ussing, O. Zinc in the anterior pituitary of rat: a histochemical and analytical work. Neuroendocrinology 45, 233–242 (1987).
Haug, F. M. Electron microscopical localization of the zinc in hippocampal mossy fibre synapses by a modified sulfide silver procedure. Histochemie 8, 355–368 (1967).
Frederickson, C. J. et al. Method for identifying neuronal cells suffering zinc toxicity by use of a novel fluorescent sensor. J. Neurosci. Methods 139, 79–89 (2004).
Shen, Y. & Yang, X. L. Zinc modulation of AMPA receptors may be relevant to splice variants in carp retina. Neurosci. Lett. 259, 177–180 (1999).
Molnar, P. & Nadler, J. V. Synaptically-released zinc inhibits N-methyl-D-aspartate receptor activation at recurrent mossy fiber synapses. Brain Res. 910, 205–207 (2001).
Zirpel, L. & Parks, T. N. Zinc inhibition of group I mGluR-mediated calcium homeostasis in auditory neurons. J. Assoc. Res. Otolaryngol. 2, 180–187 (2001).
Casagrande, S., Valle, L., Cupello, A. & Robello, M. Modulation by Zn2+ and Cd2+ of GABAA receptors of rat cerebellum granule cells in culture. Eur. Biophys. J. 32, 40–46 (2003).
Xie, X. & Smart, T. G. Giant GABAB-mediated synaptic potentials induced by zinc in the rat hippocampus: paradoxical effects of zinc on the GABAB receptor. Eur. J. Neurosci. 5, 430–436 (1993).
Connor, M. A. & Chavkin, C. Ionic zinc may function as an endogenous ligand for the haloperidol-sensitive sigma 2 receptor in rat brain. Mol. Pharmacol. 42, 471–479 (1992).
Patterson, T. A., Connor, M., Appleyard, S. M. & Chavkin, C. Oocytes from Xenopus laevis contain an intrinsic sigma 2-like binding site. Neurosci. Lett. 180, 159–162 (1994).
Hubbard, P. C. & Lummis, S. C. Zn2+ enhancement of the recombinant 5-HT3 receptor is modulated by divalent cations. Eur. J. Pharmacol. 394, 189–197 (2000).
Holst, B., Elling, C. E. & Schwartz, T. W. Metal ion-mediated agonism and agonist enhancement in melanocortin MC1 and MC4 receptors. J. Biol. Chem. 277, 47662–47670 (2002).
Tejwani, G. A. & Hanissian, S. H. Modulation of mu, delta and kappa opioid receptors in rat brain by metal ions and histidine. Neuropharmacology 29, 445–452 (1990).
Davies, P. A., Wang, W., Hales, T. G. & Kirkness, E. F. A novel class of ligand-gated ion channel is activated by Zn2+. J. Biol. Chem. 278, 712–717 (2003).
Easaw, J. C., Jassar, B. S., Harris, K. H. & Jhamandas, J. H. Zinc modulation of ionic currents in the horizontal limb of the diagonal band of Broca. Neuroscience 94, 785–795 (1999).
Green, W. N., Weiss, L. B. & Andersen, O. S. Batrachotoxin-modified sodium channels in planar lipid bilayers. Characterization of saxitoxin- and tetrodotoxin-induced channel closures. J. Gen. Physiol. 89, 873–903 (1987).
Kajita, H., Whitwell, C. & Brown, P. D. Properties of the inward-rectifying Cl− channel in rat choroid plexus: regulation by intracellular messengers and inhibition by divalent cations. Pflugers Arch. 440, 933–940 (2000).
Lin, H., Zhu, Y. J. & Lal, R. Amyloid β protein (1-40) forms calcium-permeable, Zn2+-sensitive channel in reconstituted lipid vesicles. Biochemistry 38, 11189–11196 (1999).
Spiridon, M., Kamm, D., Billups, B., Mobbs, P. & Attwell, D. Modulation by zinc of the glutamate transporters in glial cells and cones isolated from the tiger salamander retina. J. Physiol. (Lond.) 506, 363–376 (1998).
Wu, Q., Coffey, L. L. & Reith, M. E. Cations affect [3H]mazindol and [3H]WIN 35,428 binding to the human dopamine transporter in a similar fashion. J. Neurochem. 69, 1106–1118 (1997).
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A.I.B. is supported by funds from the National Institute on Aging, the National Health and Medical Research Council of Australia, the Australian Research Council Federation Fellowship, the Alzheimer's Association and the American Health Assistance Foundation
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Frederickson, C., Koh, JY. & Bush, A. The neurobiology of zinc in health and disease. Nat Rev Neurosci 6, 449–462 (2005). https://doi.org/10.1038/nrn1671
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DOI: https://doi.org/10.1038/nrn1671
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