Function of Metallothionein-3 in Neuronal Cells: Do Metal Ions Alter Expression Levels of MT3?

Bousleiman, Jamie Joe; Pinsky, Alexa M; Ki, Sohee; Su, Angela; Morozova, Irina; Kalachikov, Sergey; Wiqas, Amen; Silver, Rae; Sever, Mary J.; Austin, Rachel N.

doi:10.3390/ijms18061133

Cited by 22 publications

(20 citation statements)

References 74 publications

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“…385 Only a modest induction by metal ions was noted in human neuronal cells. 386 In macrophages the interleukins IL4 and IL13 induce MT3. 387 An in silico analysis of the complex promoters of MT genes provides information on the different binding sites of transcription factors and the differential expression of the MT genes.…”

Section: Multiplicity Of Mt Genes and Their Regulationmentioning

confidence: 99%

The Bioinorganic Chemistry of Mammalian Metallothioneins

2021

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The functions, purposes, and roles of metallothioneins have been the subject of speculations since the discovery of the protein over 60 years ago. This article guides through the history of investigations and resolves multiple contentions by providing new interpretations of the structure-stability-function relationship. It challenges the dogma that the biologically relevant structure of the mammalian proteins is only the one determined by X-ray diffraction and NMR spectroscopy. The terms metallothionein and thionein are ambiguous and insufficient to understand biological function. The proteins need to be seen in their biological context, which limits and defines the chemistry possible. They exist in multiple forms with different degrees of metalation and types of metal ions. The homoleptic thiolate coordination of mammalian metallothioneins is important for their molecular mechanism. It endows the proteins with redox activity and a specific pH dependence of their metal affinities. The proteins, therefore, also exist in different redox states of the sulfur donor ligands. Their coordination dynamics allows a vast conformational landscape for interactions with other proteins and ligands. Many fundamental signal transduction pathways regulate the expression of the dozen of human metallothionein genes. Recent advances in understanding the control of cellular zinc and copper homeostasis are the foundation for suggesting that mammalian metallothioneins provide a highly dynamic, regulated, and uniquely biological metal buffer to control the availability, fluctuations, and signaling transients of the most competitive Zn(II) and Cu(I) ions in cellular space and time.

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Section: Multiplicity Of Mt Genes and Their Regulationmentioning

confidence: 99%

The Bioinorganic Chemistry of Mammalian Metallothioneins

2021

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“…The mechanism of reduction of MT3 expression by Pb toxicity in the liver and kidney is not known. Mammalian MT3 is an unusual protein with a puzzling role (Bousleiman et al, 2017). However, the proposed mechanism may be operative here.…”

Section: Resultsmentioning

confidence: 86%

The protective role of Coenzyme Q10 in metallothionein-3 expression in liver and kidney upon rats’ exposure to lead acetate

Mazandaran

Khodarahmi

2021

Mol Biol Rep

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Metallothionein-3 (MT3) is an antioxidant protein that alters after exposure to heavy metals. In this study, we investigated the hepatic and renal expression of MT3 gene following exposure to lead acetate (PbAc) alone and PbAc plus CoQ10 as an adjuvant antioxidant. Twenty-four rats were allocated into three groups, including control, PbAc (free access to drinking water contaminated with PbAc at 1g/100ml), and PbAc plus CoQ10 (10 mg/kg/day Oral). After 28 consecutive days of treatment, the mRNA expression of MT3 and Cyt-c genes and MT3 protein levels were assessed using real-time PCR and immunosorbent assay. The serum lipid pro le was also monitored in the three groups. PbAc exposure signi cantly reduced the hepatic and renal MT3 mRNA and protein expression compared to the control group. This reduction was signi cantly increased with addition of CoQ10 to levels near those of the control group. The hepatic and renal expression of Cyt-c mRNA increased after treatment with PbAc, while such effect was reversed after addition of CoQ10. Alteration in lipid pro le including increased cholesterol and lowdensity lipoprotein levels were observed after PbAc exposure which were counteracted by CoQ10. Our results con rm the cytotoxic effects of acute lead exposure manifested as changes in the serum lipid pro le and cellular levels of Cyt-c mRNA. These cytotoxic effects may have been caused by decreased MT3 gene expression and be reduced by the protective role of CoQ10.

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“…ZnT3 transports zinc into synaptic vesicle membranes of glutamatergic neurons in the mossy fibre region of the DG. Prior work suggests that this regulation happens at the protein level, either by regulating protein expression from mRNA or protein degradation (Bousleiman et al., ). Studies of other zinc regulatory proteins namely Zip4 and Zip5, in the intestine, pancreas and visceral yolk sac, indicate that the expression of these zinc transporters can be modified post‐transcriptionally (Weaver, Dufner‐Beattie, Kambe, & Andrews, ).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the present work suggests that mast cells, or something they produce or neutralize, impact ZnT3 levels, which in turn controls vesicular zinc content (Linkous et al., ). Furthermore, we hypothesize that ZnT3 is post‐translationally regulated so the connection between mast cells and ZnT3 levels must be mediated by a factor that affects protein levels (Bousleiman et al., ; Lee, Kim, Hong et al., ). Perhaps in the absence of mast cells, the brain synthesizes (or fails to degrade) more ZnT3 in order to put excess zinc into neuronal vesicles.…”

Section: Discussionmentioning

confidence: 99%

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Elevated zinc transporter ZnT3 in the dentate gyrus of mast cell‐deficient mice

Wiqas

LeSauter

Taub

et al. 2019

Eur J of Neuroscience

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Zinc is important in neurogenesis, but excessive levels can cause apoptosis and other pathologies leading to cognitive impairments. Mast cells are present in many brain regions including the hippocampus, an area rich in vesicular zinc. Mast cells contain zinc‐rich granules and a well‐developed mechanism for uptake of zinc ions; both features point to the potential for a role in zinc homeostasis. Prior work using the Timm stain supported this hypothesis, as increased labile zinc was detected in the hippocampus of mast cell‐deficient mice compared to wild‐type mice while no differences in total zinc were found between the two genotypes in the whole brain or other tissues. The current report further examines differences in zinc homeostasis between wild‐type and mast cell‐deficient mice by exploring the zinc transporter ZnT3, which transports labile zinc into synaptic vesicles. The first study used immunocytochemistry to localize ZnT3 within the mossy fibre layer of the hippocampus to determine whether there was differential expression of ZnT3 in wild‐type versus mast cell‐deficient mice. The second study used inductively coupled plasma mass spectrometry (ICP‐MS) to determine total zinc content in the whole dentate gyrus of the two genotypes. The immunocytochemical results indicate that there are higher levels of ZnT3 localized to the mossy fibre layer of the dentate gyrus of mast cell‐deficient mice than in wild‐type mice. The ICP‐MS data reveal no differences in total zinc in dentate gyrus as a whole. The results are consistent with the hypothesis that mast cells participate in zinc homeostasis at the level of synaptic vesicles.

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Function of Metallothionein-3 in Neuronal Cells: Do Metal Ions Alter Expression Levels of MT3?

Cited by 22 publications

References 74 publications

The Bioinorganic Chemistry of Mammalian Metallothioneins

The Bioinorganic Chemistry of Mammalian Metallothioneins

The protective role of Coenzyme Q10 in metallothionein-3 expression in liver and kidney upon rats’ exposure to lead acetate

Elevated zinc transporter ZnT3 in the dentate gyrus of mast cell‐deficient mice

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