Copper Modulation of NMDA Responses in Mouse and Rat Cultured Hippocampal Neurons

Vlachová, Viktorie; Zemková, Hana; Vyklický, Ladislav

doi:10.1111/j.1460-9568.1996.tb01189.x

Cited by 97 publications

(68 citation statements)

References 30 publications

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“…1) without affecting the distribution or localization of NMDA receptors (data not shown), indicating a direct effect on NMDA receptor function or downstream signaling. Consistent with this, exogenously applied copper can inhibit NMDA receptor-mediated current in hippocampal neurons (24)(25)(26) and can selectively reduce NMDA-mediated potentials and synaptic plasticity in hippocampal slices (27). Importantly, the concentration of copper here shown to protect hippocampal neu- Lysates from injured (L) and uninjured (R) hippocampus of wild-type and Mo br (Ϫ͞Y) littermates were subjected to SDS͞PAGE, transferred to Immobilon P membranes, and stained with primary antibody against spectrin and the caspase 3-dependent p120 cleavage product, as well as the p145 and p150 calpain-dependent cleavage products.…”

Section: Discussionmentioning

confidence: 63%

Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

Schlief

West

Craig

et al. 2006

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

164

129

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Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia, and failure to thrive, is due to inherited loss-of-function mutations in the gene encoding a copper-transporting ATPase (Atp7a) on the X chromosome. Although affected patients exhibit signs and symptoms of copper deficiency, the mechanisms resulting in neurologic disease remain unknown. We recently discovered that Atp7a is required for the production of an NMDA receptor-dependent releasable copper pool within hippocampal neurons, a finding that suggests a role for copper in activity-dependent modulation of synaptic activity. In support of this hypothesis, we now demonstrate that copper chelation exacerbates NMDA-mediated excitotoxic cell death in primary hippocampal neurons, whereas the addition of copper is specifically protective and results in a significant decrease in cytoplasmic Ca 2؉ levels after NMDA receptor activation. Consistent with the known neuroprotective effect of NMDA receptor nitrosylation, we show here that this protective effect of copper depends on endogenous nitric oxide production in hippocampal neurons, demonstrating in vivo links among neuroprotection, copper metabolism, and nitrosylation. Atp7a is required for these copper-dependent effects: Hippocampal neurons isolated from newborn Mo br mice reveal a marked sensitivity to endogenous glutamate-mediated NMDA receptor-dependent excitotoxicity in vitro, and mild hypoxic͞isch-emic insult to these mice in vivo results in significantly increased caspase 3 activation and neuronal injury. Taken together, these data reveal a unique connection between copper homeostasis and NMDA receptor activity that is of broad relevance to the processes of synaptic plasticity and excitotoxic cell death.excitotoxicity ͉ Menkes disease ͉ brain ͉ newborn

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Section: Discussionmentioning

confidence: 63%

Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

Schlief

West

Craig

et al. 2006

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

164

129

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“…This effect of Mn 2+ on brain Cu 2+ concentrations appears to have some degree of regional brain selectivity as Cu 2+ concentrations in the white matter of the same Mn 2+ -exposed non-human primates were not increased . Cu 2+ is also a potent NMDA receptor antagonist as defined in our present study and in previous electrophysiological studies (Vlachova et al, 1996;Trombley and Shepherd, 1996). Similar to Mn 2+ , Cu 2+ is released from nerve terminals following depolarization (Kardos et al, 1989) and it is known to inhibit NMDA receptors (Vlachova et al, 1996) and long-term potentiation in hippocampal slices (Doreulee et al, 1997).…”

Section: Discussionmentioning

confidence: 64%

“…Cu 2+ is also a potent NMDA receptor antagonist as defined in our present study and in previous electrophysiological studies (Vlachova et al, 1996;Trombley and Shepherd, 1996). Similar to Mn 2+ , Cu 2+ is released from nerve terminals following depolarization (Kardos et al, 1989) and it is known to inhibit NMDA receptors (Vlachova et al, 1996) and long-term potentiation in hippocampal slices (Doreulee et al, 1997). Therefore, chronic exposure to elevated levels of Mn 2+ may inhibit NMDA receptor dependent cellular function not only by increasing endogenous levels of Mn 2+ but also of Cu 2+ .…”

Section: Discussionmentioning

confidence: 64%

“…Mayer and Westbrook (1987) showed that in hippocampal neurons Mn 2+ produces a strong voltage-dependent block of responses to NMDA. This is similar to the channel block produced by Mg 2+ but different to the voltage-independent inhibition of the NMDA receptor by other physiologically relevant divalent cations such as Zn 2+ (Christine and Choi, 1990) and Cu 2+ (Vlachova et al, 1996) as well as the environmental neurotoxicant Pb 2+ (Alkondon et al, 1990;Guilarte et al, 1995;Guilarte, 1997). Therefore, divalent cations are important regulators of NMDA receptor function and they interact at distinct and different sites on the NMDA receptor protein.…”

Section: Discussionmentioning

confidence: 78%

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Manganese inhibits NMDA receptor channel function: Implications to psychiatric and cognitive effects

Guilarte

Chen

2007

NeuroToxicology

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Humans exposed to excess levels of manganese (Mn 2+ ) express psychiatric problems and deficits in attention and learning and memory. However, there is a paucity of knowledge on molecular mechanisms by which Mn 2+ produces such effects. We now report that Mn 2+ is a potent inhibitor of [ 3 H]-MK-801 binding to the NMDA receptor channel in rat neuronal membrane preparations. The inhibition of [ 3 H]-MK-801 to the NMDA receptor channel by Mn 2+ was activity-dependent since Mn 2+ was a more potent inhibitor in the presence of the NMDA receptor co-agonists glutamate and glycine (K i = 35.9 ± 3.1 μM) than in their absence (K i = 157.1 ± 6.5 μM). We also show that Mn 2+ is a NMDA receptor channel blocker since its inhibition of [ 3 H]-MK-801 binding to the NMDA receptor channel is competitive in nature. That is, Mn 2+ significantly increased the affinity constant (K d ) with no significant effect on the maximal number of [ 3 H]-MK-801 binding sites (B max ). Under stimulating conditions, Mn 2+ was equipotent in inhibiting [ 3 H]-MK-801 binding to NMDA receptors expressed in neuronal membrane preparations from different brain regions. However, under basal, non-stimulated conditions, Mn 2+ was more potent in inhibiting NMDA receptors in the cerebellum than other brain regions. We have previously shown that chronic Mn 2+ exposure in non-human primates increases Cu 2+ , but not zinc or iron concentrations in the basal ganglia (Guilarte et al., Experimental Neurology 202: 381-390, 2006). Therefore, we also tested the inhibitory effects of Cu 2+ on [ 3 H]-MK-801 binding to the NMDA receptor channel. The data shows that Cu 2+ in the presence of glutamate and glycine is a more potent inhibitor of the NMDA receptor than Mn 2+ . Our findings suggest that the inhibitory effect of Mn 2+ and/or Cu 2+ on the NMDA receptor may produce a deficit in glutamatergic transmission in the brain of individuals exposed to excess levels of Mn 2+ and produce neurological dysfunction.

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“…Stimulation of the NMDA receptor (NMDA-R) evokes the release of copper in hippocampal neurons and is associated with a repositioning of the ATP7A transporter towards the hyperactive sites [41]. Copper interacts closely with the NMDA-R and may inhibit currents related to NMDA-R activation [42]. Copper acts on the S-nitrosylation of the NMDA receptor [43].…”

Section: Copper and Synapses In The Cnsmentioning

confidence: 99%

Abnormal Copper Homeostasis: Mechanisms and Roles in Neurodegeneration

Manto

2014

Toxics

103

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As a cofactor of proteins and enzymes involved in critical molecular pathways in mammals and low eukaryotes, copper is a transition metal essential for life. The intra-cellular and extra-cellular metabolism of copper is under tight control, in order to maintain free copper concentrations at very low levels. Copper is a critical element for major neuronal functions, and the central nervous system is a major target of disorders of copper metabolism. Both the accumulation of copper and copper deficiency are associated with brain dysfunction. The redox capacities of free copper, its ability to trigger the production of reactive oxygen species and the close relationships with the regulation of iron and zinc are remarkable features. Major advances in our understanding of the relationships between copper, neuronal functions and neurodegeneration have occurred these last two decades. The metabolism of copper and the current knowledge on the consequences of copper dysregulation on brain disorders are reviewed, with a focus on neurodegenerative diseases, such as Wilson's disease, Alzheimer's disease and Parkinson's disease. In vitro studies, in vivo experiments and evidence from clinical observations of the neurotoxic effects of copper provide the basis for future therapies targeting copper homeostasis.

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Copper Modulation of NMDA Responses in Mouse and Rat Cultured Hippocampal Neurons

Cited by 97 publications

References 30 publications

Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

Manganese inhibits NMDA receptor channel function: Implications to psychiatric and cognitive effects

Abnormal Copper Homeostasis: Mechanisms and Roles in Neurodegeneration

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