Differential modulation by zinc and copper of amino acid receptors from rat olfactory bulb neurons

Trombley, Paul Q.; Shepherd, G. M.

doi:10.1152/jn.1996.76.4.2536

Cited by 114 publications

(103 citation statements)

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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: Discussionsupporting

confidence: 65%

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: Discussionsupporting

confidence: 65%

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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“…Its role in enzyme catalysis and gene expression is well established. More recently it has been demonstrated that copper can regulate brain ligand-gated ion channels (17,18). Here we show that copper is also a potent reversible inhibitor of both water and glycerol transport of the aquaglyceroporin AQP3.…”

Section: Discussionsupporting

confidence: 48%

Copper Inhibits the Water and Glycerol Permeability of Aquaporin-3

Zelenina

Tritto

Bondar

et al. 2004

Journal of Biological Chemistry

123

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Aquaporin-3 (AQP3) is an aquaglyceroporin expressed in erythrocytes and several other tissues. Erythrocytes are, together with kidney and liver, the main targets for copper toxicity. Here we report that both water and glycerol permeability of human AQP3 is inhibited by copper. Inhibition is fast, dose-dependent, and reversible. If copper is dissolved in carbonic acid-bicarbonate buffer, the natural buffer system in our body, doses in the range of those observed in Wilson disease and in copper poisoning caused significant inhibition. AQP7, another aquaglyceroporin, was insensitive to copper. Copper is an essential trace element in the human body. It is present in the blood and is incorporated in several vital proteins, such as Cu,Zn-SOD, dopamine ␤-hydroxylase, ceruloplasmin, cytochrome c oxidase, etc. (recently reviewed in Ref. 1). Blood levels of copper are increased in several pathological conditions, such as Wilson disease, Indian childhood cirrhosis, juvenile rheumatoid arthritis, thalassemia, and sickle cell anemia (1-5).Aquaporin-3 (AQP3) 1 is an aquaglyceroporin expressed in several mammalian tissues including erythrocytes (6 -12). It is well established that erythrocytes are permeable for glycerol, but the molecular mechanism for this effect is still obscure. It is also well established that glycerol permeability of erythrocytes is extremely sensitive to copper. We have recently shown that AQP3 water permeability is sensitive to nickel (13). Here we report that copper is a potent inhibitor of AQP3 permeability for glycerol and water. We expressed AQP3 in a human cell line and tested the effect of copper on glycerol and water permeability of the transfected cells. Three extracellular amino acid residues were found to be responsible for the copper sensitivity. We modeled the situation when AQP3 is co-expressed with another AQP, not permeable for glycerol, and found that only glycerol but not water permeability will be inhibited by copper in such cells. The results of this study provide a better understanding of processes that occur in severe copper metabolism defects and copper poisoning. MATERIALS AND METHODScDNA Constructs-The constructs for expression of human AQP3 (wild type and mutants) and the long form of AQP4 have been described previously (13). cDNA fragments encoding full-length AQP3 and AQP4 were obtained by amplification from the human lung QUICK-Clone cDNA library (Clontech). cDNA encoding mouse AQP7 was a kind gift from J. M. Carbrey and P. Agre (Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD). The cDNA fragments were subcloned in-frame into the pEGFP-N2 vector for AQP3 tagged with green fluorescent protein (GFP) at the COOH terminus into pIRES2-EGFP vector (Clontech) for AQP3 and GFP expressed in the same cell as separate proteins and into the pEGFP-C2 vector for AQP4 and AQP7 tagged with GFP at NH 2 termini. The point mutations in extracellular loops of human AQP3 were generated by PCR-based mutagenesis using wild-type cDNA as a template and c...

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“…Copper and zinc also modulate other members of the P2X family of receptors, but their effects depend on the receptor subtype. For example, both zinc and copper facilitate the ATP-evoked responses on the P2X 2 receptor (14,15) whereas in the P2X 7 receptor, copper inhibits the ATP-gated currents, whereas zinc is virtually without effect (13). These findings further support the notion that the P2X purinoceptors may have separate metal-binding sites to modulate the channel activity.…”

mentioning

confidence: 52%

“…Zinc is well characterized as a modulator of glutamate neurotransmission, particularly via N-methyl-D-aspartate receptors (1,7). Zinc and copper may also interact with voltage-gated ionic channels and may be important contributors to brain excitability (33).…”

Section: Discussionmentioning

confidence: 99%

“…The importance of trace metals in synaptic activity is highlighted by the description that both copper and zinc are stored in synaptic vesicles from where they are released by electrical depolarization, reaching a high micromolar concentration at the synaptic cleft (2)(3)(4). Trace metals are known to modulate a wide variety of brain ionotropic receptors such as glycine, N-methyl-D-aspartate, ␥-aminobutyric acid, nicotinic, and the novel nucleotide receptors (P2X) family (5)(6)(7)(8)(9). The P2X purinoceptors are homomeric or heteromeric membrane channels gated by extracellular ATP and related synthetic nucleotides; North (10) recently reviewed the principles of the molecular physiology of this family of receptors.…”

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confidence: 99%

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Histidine 140 Plays a Key Role in the Inhibitory Modulation of the P2X4 Nucleotide Receptor by Copper but Not Zinc

Coddou

Morales

González

et al. 2003

Journal of Biological Chemistry

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To elucidate the role of extracellular histidines in the modulation of the rat P2X 4 receptor by trace metals, we generated single, double, and triple histidine mutants for residues 140, 241, and 286, replacing them with alanines. cDNAs for the wild-type and receptor mutants were expressed in Xenopus laevis oocytes and in human embryonic kidney 293 cells and examined by the two electrode and patch clamp techniques, respectively. Whereas copper inhibited concentration-dependently the ATP-gated currents in the wild-type and in the single or double H241A and H286A receptor mutants, all receptors containing H140A were insensitive to copper in both cell systems. The characteristic bell-shaped concentration-response curve of zinc observed in the wildtype receptor became sigmoid in both oocytes and human embryonic kidney cells expressing the H140A mutant; in these mutants, the zinc potentiation was 2.5-4-fold larger than in the wild-type. Results with the H140T and H140R mutants further support the importance of a histidine residue at this position. We conclude that His-140 is critical for the action of copper, indicating that this histidine residue, but not His-241 or His-286, forms part of the inhibitory allosteric metal-binding site of the P2X 4 receptor, which is distinct from the putative zinc facilitator binding site.The notion that trace metals such as zinc or copper are atypical brain messengers has attracted much attention in view of their emerging role in the modulation of brain excitability (1). The importance of trace metals in synaptic activity is highlighted by the description that both copper and zinc are stored in synaptic vesicles from where they are released by electrical depolarization, reaching a high micromolar concentration at the synaptic cleft (2-4). Trace metals are known to modulate a wide variety of brain ionotropic receptors such as glycine, N-methyl-D-aspartate, ␥-aminobutyric acid, nicotinic, and the novel nucleotide receptors (P2X) family (5-9). The P2X purinoceptors are homomeric or heteromeric membrane channels gated by extracellular ATP and related synthetic nucleotides; North (10) recently reviewed the principles of the molecular physiology of this family of receptors. Within the P2X receptor family, the P2X 4 is the most widely distributed in the central nervous system, including the cerebellum and the CA1 region of the hippocampus, where it has been proposed to play a role in glutamatergic synapses (11).The P2X 4 receptor is an interesting model of an ionic channel differentially modulated by trace metals. Acuñ a-Castillo et al. (12) and Coddou et al. (13) reported that zinc potentiates the ATP-evoked currents whereas copper has an inhibitory effect on the activity of this receptor. Based on these findings, Acuñ aCastillo et al. (12) proposed that trace metals modulate the activity of the P2X 4 receptor via two separate metal-binding sites. One of these sites has a preferential selectivity for copper and is characterized by a non-competitive inhibition of the ATP-gated channel acti...

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Differential modulation by zinc and copper of amino acid receptors from rat olfactory bulb neurons

Cited by 114 publications

References 0 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

Copper Inhibits the Water and Glycerol Permeability of Aquaporin-3

Histidine 140 Plays a Key Role in the Inhibitory Modulation of the P2X4 Nucleotide Receptor by Copper but Not Zinc

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