N<scp>OVEL</scp>N<scp>EURAL</scp>M<scp>ODULATORS</scp>

Boehning, Darren; Snyder, Solomon H.

doi:10.1146/annurev.neuro.26.041002.131047

Cited by 925 publications

(359 citation statements)

References 154 publications

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“…Redox modulation by nitric oxide is a well recognized mechanism of regulation of NMDA receptors involving nitrosylation at specific cysteine residues (18,19). Given the role of copper as an electron source for thiol chemistry determining nitrosylation specificity (20), we hypothesized a role for nitric oxide in the neuroprotective effect of copper against NMDA receptor-mediated excitotoxicity.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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 neuronal localization seen in the present study, especially the low level of expression seen in hippocampal pyramidal neurons in control tissue and cultured neuronal cells, raises the possibility that enzyme performs an essential physiological function. In this regard, myeloperoxidase may prove to be analogous to nitric oxide synthase, another enzyme present in white blood cells with a role in host defenses, that plays a separate role in neurotransmission in the CNS (Boehning and Snyder 2003).…”

Section: Discussionmentioning

confidence: 99%

Neuronal expression of myeloperoxidase is increased in Alzheimer's disease

Green

Mendez

Jacob

et al. 2004

Journal of Neurochemistry

290

196

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Myeloperoxidase, a heme protein expressed by professional phagocytic cells, generates an array of oxidants which are proposed to contribute to tissue damage during inflammation. We now report that enzymatically active myeloperoxidase and its characteristic amino acid oxidation products are present in human brain. Further, expression of myeloperoxidase is increased in brain tissue showing Alzheimer's neuropathology. Consistent with expression in phagocytic cells, myeloperoxidase immunoreactivity was present in some activated microglia in Alzheimer brains. However, the majority of immunoreactive material in brain localized with amyloid plaques and, surprisingly, neurons including granule and pyramidal neurons of the hippocampus. Confirming neuronal localization of the enzyme, several neuronal cell lines as well as primary neuronal cultures expressed myeloperoxidase protein. Myeloperoxidase mRNA was also detected in neuronal cell lines. These results reveal the unexpected presence of myeloperoxidase in neurons. The increase in neuronal myeloperoxidase expression we observed in Alzheimer disease brains raises the possibility that the enzyme contributes to the oxidative stress implicated in the pathogenesis of the neurodegenerative disorder.

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“…However, recent findings point to the involvement of NO Å in signalling pathways independent of cGMP production (Boehning and Snyder, 2003) (Fig. 1).…”

Section: Nitric Oxide Targets In Physiologic and Pathophysiologic Patmentioning

confidence: 96%

Nitric oxide in brain: diffusion, targets and concentration dynamics in hippocampal subregions

Ledo

Frade

Barbosa

et al. 2004

Molecular Aspects of Medicine

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Nitric oxide (NO Å ) is a diffusible regulatory molecule involved in a wide range of physiological and pathological events. At the tissue level, a local and temporary increase in NO Å concentration is translated into a cellular signal. From our current knowledge of biological synthesis and decay, the kinetics and mechanisms that determine NO Å concentration dynamics in tissues are poorly understood. Generally, NO Å mediates its effects by stimulating (e.g., guanylate cyclase) or inhibiting (e.g., cytochrome oxidase) transition metal-containing proteins and by post-translational modification of proteins (e.g., formation of nitrosothiol adducts). The borderline between the physiological and pathological activities of NO Å is a matter of controversy, but tissue redox environment, supramolecular organization and compartmentalisation of NO Å targets are important features in determining NO Å actions. In brain, NO Å synthesis in the dependency of glutamate NMDA receptor is a paradigmatic example; the NMDA-subtype glutamate receptor triggers intracellular signalling pathways that govern neuronal plasticity, development, senescence and disease, suggesting a role for NO Å in these processes. Measurements of NO Å in the different subregions of hippocampus, in a glutamate NMDA receptor-dependent fashion, by means of electrochemical selective microsensors illustrate the concentration dynamics of NO Å in the sub-regions of this brain area. The analysis of NO Å concentration-time profiles in the hippocampus requires consideration of at least two interrelated issues, also addressed in this review. NO Å diffusion in a biological medium and regulation of NO Å activity. Ó 2004 Elsevier Ltd. All rights reserved.Abbreviations: CAPON, Carboxy-terminal PDZ ligand of nNOS; DOPAC, dihydroxyphenylacetic acid; EPR, electron paramagnetic resonance; LTP, long-term potentiation; NMDA, N-methyl-D D -aspartate; NOS, nitric oxide synthase; PDZ, PSD-95 discs large/ZO-1 homology domain; PSD-95, post-synaptic density protein 95

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NOVELNEURALMODULATORS

Cited by 925 publications

References 154 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

Neuronal expression of myeloperoxidase is increased in Alzheimer's disease

Nitric oxide in brain: diffusion, targets and concentration dynamics in hippocampal subregions

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