A Menkes P-type ATPase involved in copper homeostasis in the central nervous system of the rat

Qian, Yongchang; Tiffany‐Castiglioni, Evelyn; Harris, Edward D.

doi:10.1016/s0169-328x(97)00083-1

Cited by 29 publications

(16 citation statements)

References 35 publications

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“…Also the level of DMT1 is decreased, at least in CaCo-2 cells, following exposure to copper [41]. In addition, a rising cellular copper content induces the translocation of the copper transporting ATPase ATP7A [42] into the plasma membrane of chinese hamster ovary cells, human fibroblasts and HeLa cells, thereby facilitating copper export [43,44]. Similar alterations of the location of these proteins, which are involved in copper transport and are expressed in astrocyte cultures [17,45], would lower copper accumulation and increase copper export, thereby generating a steady state level of cellular copper.…”

Section: Discussionmentioning

confidence: 99%

Copper Accelerates Glycolytic Flux in Cultured Astrocytes

Scheiber

Dringen

2011

Neurochem Res

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Astrocyte-rich primary cultures were used to investigate the consequences of a copper exposure on the glucose metabolism of astrocytes. After application of CuCl(2) (30 μM) the specific cellular copper content increased from initial 1.5 ± 0.2 nmol/mg to a steady state level of 7.9 ± 0.9 nmol/mg within about 12 h. The copper accumulation was accompanied by a significant increase in the extracellular lactate concentration. The stimulating effect of copper on the lactate production remained after removal of extracellular copper. Copper treatment accelerated the rates of both glucose consumption and lactate production by about 60%. The copper induced acceleration of glycolytic flux was prevented by inhibition of protein synthesis, and additive to the stimulation of glycolysis observed for inhibitors of respiration or prolyl hydroxylases. A copper induced stimulation of glycolytic flux in astrocytes could have severe consequences for the glucose metabolism of the brain in conditions of copper overload.

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Section: Discussionmentioning

confidence: 99%

Copper Accelerates Glycolytic Flux in Cultured Astrocytes

Scheiber

Dringen

2011

Neurochem Res

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“…The Atp7a regulates Cu release from astroglial cells (45). It is thought that Cu binding to the HMB domain of Atp7a is a critical step for Cu transport (36).…”

Section: Discussionmentioning

confidence: 99%

The Involvement of Copper Transporter in Lead-induced Oxidative Stress in Astroglia

et al. 2005

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Lead (Pb), depositing primarily in astroglia in the brain, is a well-known neurotoxicant and a risk factor for neurologic disorders. Pb has been reported to induce oxidative stress by probably the disturbance of copper (Cu) homeostasis in astroglia. Thus, we hypothesized that Pb-induced oxidative stress is initiated by interfering with Cu transporter in astroglia. In this study, we observed Pb-induced oxidative stress as indicated by reactive oxygen species (ROS) augmentation and GRP78 and GRP94 protein induction, and it was parallel to Cu accumulation intracellularly by Pb. To further address Cu transporter as a potential Pb target, a heavy metal-binding (HMB) domain of Cu-transporting ATPase (Atp7a) was overexpressed and purified. Evidence showed that one molecule of HMB chelated 11 Pb ions or seven Cu ions and that Pb competed with Cu for binding to HMB. These findings suggest that Pb-induced oxidative stress results from the impairment of Cu metabolism by Pb targeting of Atp7a.

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“…In contrast, Hg specifically targets sulfhydryl or thiol groups of proteins to induce oxidative stress (Guo et al, 1998). Organic mercury, p-chloromer-curibenzoate (PCMB), also blocks copper release from cells (Qian et al, 1995(Qian et al, , 1997(Qian et al, , 1998. The ability of both metals to modulate protein binding activities to GST-Ya ARE/EpRE, NF-~:B, Ha-ras ARE/EpRE, and AP-1 consensus binding sequences raises the intriguing possibility that modulation of grp78 expression by metals involves a transcriptional mechanism mediated by redox-regulated transcription factors, even though some different responses of binding activities to these factors were observed between Pb and Hg-exposed cells (Figs.…”

Section: Discussionmentioning

confidence: 99%

Induction of 78 kD glucose-regulated protein (GRP78) expression and redox-regulated transcription factor activity by lead and mercury in C6 rat glioma cells

et al. 2001

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Lead (Pb) and mercury (Hg) are widespread environmental contaminants that induce prominent neural toxicity. Although the brain is not the major Pb and Hg depot in the body, these metals preferentially accumulate in astroglia to exert toxic effects. In this study, we examined the effects of Pb acetate and HgCl(2) on the expression of GRP78, a molecular chaperone in the endoplasmic reticulum (ER) that may provide cytoprotection in response to cellular stresses in the C6 rat glioma cell line. We also evaluated the DNA binding activities of several redox-regulated transcription factors in metal-treated cells. Our results showed that mRNA levels of GRP78 were up-regulated by Pb and Hg at 0.1 and 1 micro M, but down-regulated at higher concentrations (10 micro M). GRP78 protein levels increased in a concentration- and time-dependent manner in Pb and/or Hg-treated cells. Pb increased protein binding to the GST- Upsilon a antioxidant/electrophile response element (ARE/EpRE) and to the NF- kappaB consensus binding sequence of the cytomegalovirus 2 (CMB2) promoter, but decreased protein binding to the Ha-ras ARE/EpRE or to the c-fos 12-O-tetradecanoyl-phorbol-13-acetate (TPA) response element (TRE). In contrast, Hg activated DNA binding by all redox-regulated transcription factors. These studies shed some light on the molecular mechanisms of Pb and Hg toxicity in C6 rat glioma cells and suggest that GRP78 and oxidative stress may participate in the neurotoxic response to these metals.

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A Menkes P-type ATPase involved in copper homeostasis in the central nervous system of the rat

Cited by 29 publications

References 35 publications

Copper Accelerates Glycolytic Flux in Cultured Astrocytes

Copper Accelerates Glycolytic Flux in Cultured Astrocytes

The Involvement of Copper Transporter in Lead-induced Oxidative Stress in Astroglia

Induction of 78 kD glucose-regulated protein (GRP78) expression and redox-regulated transcription factor activity by lead and mercury in C6 rat glioma cells

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