NMDA Receptor Activation Mediates Copper Homeostasis in Hippocampal Neurons

Schlief, Michelle L.; Craig, Ann Marie; Gitlin, Jonathan D.

doi:10.1523/jneurosci.3699-04.2005

Cited by 273 publications

(254 citation statements)

References 40 publications

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“…In children with Menkes disease, an impairment in copper acquisition in utero due to loss-of-function mutations in the gene encoding a coppertransporting ATPase, Atp7a, results in fatal neurodegeneration associated with intractable seizures, severe hypotonia, and profound developmental delay (8). Pathologic analysis of brain tissue from affected patients reveals neurodegeneration in the cerebral cortex, cerebellum, and hippocampus, consistent with the known sites of the expression of Atp7a within the developing central nervous system (9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 74%

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.

167

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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mentioning

confidence: 74%

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.

167

129

View full text Add to dashboard Cite

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“…The co-release of copper and Aβ might make them available for pathological interactions. The concentration of copper in the glutamatergic synaptic cleft approximates 15 μM [183,184], and copper in the synapse can modulate glutamateric signaling by causing s-nitrosylationdependent inhibition of the NMDA signaling [185,186], contributing to glutamatergic dysfunction in the disease [181].…”

Section: Coppermentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…20 It is, thus, likely that seizures and neuronal degeneration observed in MD patients may also be related to a disturbed neuronal transmission through impaired function of NMDA receptors. 20 STRUCTURE OF THE ATP7A PROTEIN ATP7A (and ATP7B) is a member of a large family of P-type ATPases that are energy-utilizing membrane proteins functioning as cation pumps ( Figure 5) (reviewed by Lutsenko et al 22 ). They are called 'P-type' ATPases, as they form a phosphorylated intermediate during the transport of cations across a membrane.…”

Section: Cellular Copper Metabolismmentioning

confidence: 99%