Spontaneous, synchronous zinc spikes oscillate with neural excitability and calcium spikes in primary hippocampal neuron culture

Zhang, Chen; Maslar, Drew; Minckley, Taylor; LeJeune, Kate D.; Qin, Yan

doi:10.1111/jnc.15334

Cited by 12 publications

(17 citation statements)

References 92 publications

(164 reference statements)

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“…Thus, buffering must allow zinc signals to occur, reach their targets, and then restore concentrations to steady-state levels. On the one hand, MT is a source of signaling Zn(II) ions when it transduces redox signals into zinc signals or possibly as result of local pH changes due to an inherent pH dependence of the Zn(II) affinity. , T, on the other hand, removes Zn(II) ions from sites that are targets of the signaling Zn(II) ions.…”

Section: Relating Metallothionein Thermodynamics and Kinetics To Cont...mentioning

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: Relating Metallothionein Thermodynamics and Kinetics To Cont...mentioning

confidence: 99%

The Bioinorganic Chemistry of Mammalian Metallothioneins

2021

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“…Indeed, the concentration of glutamate in the synaptic cleft is estimated to reach the mM range after neuronal depolarization. Although the level of Zn increases to approximately 10 nM in the CSF under ischemic conditions, the Zn concentration in synapses is estimated to be 1–100 μM.‍ ( 28 ) Zhang et al ‍ ( 29 ) observed a spontaneous and synchronous “Zn spike” in cultured hippocampal neurons along with calcium (Ca) spikes. In such situations, the Zn concentration in synapses may become much higher.…”

Section: Roles Of Cu and Zn In The Synapsementioning

confidence: 99%

Crosstalk of copper and zinc in the pathogenesis of vascular dementia

Kawahara

Tanaka

Kato-Negishi

2022

J. Clin. Biochem. Nutr.

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Copper and zinc are essential for normal brain functions. Both are localized in presynaptic vesicles and are secreted into synaptic clefts during neuronal excitation. Despite their significance, excesses of copper and zinc are neurotoxic. In particular, excess zinc after transient global ischemia plays a central role in the ischemia-induced neurodegeneration and pathogenesis of vascular type senile dementia. We previously found that sub-lethal concentrations of copper remarkably exacerbated zinc-induced neurotoxicity, and we investigated the molecular pathways of copper-enhanced zinc-induced neurotoxicity. The endoplasmic reticulum stress pathway, the stress-activated protein kinases/ c-Jun amino-terminal kinases pathway, and mitochondrial energy production failure were revealed to be involved in the neurodegenerative processes. Regarding the upstream factors of these pathways, we focused on copper-derived reactive oxygen species and the disruption of calcium homeostasis. Because excess copper and zinc may be present in the synaptic clefts during ischemia, it is possible that secreted copper and copper-induced reactive oxygen species may enhance zinc neurotoxicity and eventually contribute to the pathogenesis of vascular type senile dementia.

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“…Elucidation of zinc's role in physiological or pathological conditions is particularly challenging because its multiple roles in cellular processes, [5,6,22]; its possible overlap with Ca, [23], and its mobility between "chelatable" and "non-chelatable" pools. ( [6].…”

Section: Metalsmentioning

confidence: 99%

Effects of Zinc, Mercury, or Lead on [3H]MK-801 and [3H]Fluorowillardiine Binding to Rat Synaptic Membranes

et al. 2021

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Glutamate (Glu) is considered the most important excitatory amino acid neurotransmitter in the mammalian Central Nervous System. Zinc (Zn) is co-released with Glu during synaptic transmission and interacts with Glutamate receptors and transporters. We performed binding experiments using [ 3 H]MK-801 (NMDA), and [ 3 H]Fluorowillardine (AMPA) as ligands to study Zn-Glutamate interactions in rat cortical synaptic membranes. We also examined the effects of mercury and lead on NMDA or AMPA receptors. Zinc at 1 nM, significantly potentiates [ 3 H]MK-801 binding. Lead inhibits [ 3 H]MK-801 binding at micromolar concentrations. At millimolar concentrations, Hg also has a significant inhibitory effect. These effects are not reversed by Zn (1 nM). Zinc displaces the [ 3 H]FW binding curve to the right. Lead (nM) and Hg (μM) inhibit [ 3 H]FW binding. At certain concentrations, Zn reverses the effects of these metals on [ 3 H]FW binding. These specific interactions serve to clarify the role of Zn, Hg, and Pb in physiological and pathological conditions.Abbreviations Glu Glutamate NMDA (2R)-2-(methylamino)butanedioic acid AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid MK-801 (5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine FW 5-Fluorowillardiine 2-amino-3-(5-fluoro-2,4-dioxopyrimidin-1-yl)propanoic acid * J. G. Ortiz

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Spontaneous, synchronous zinc spikes oscillate with neural excitability and calcium spikes in primary hippocampal neuron culture

Cited by 12 publications

References 92 publications

The Bioinorganic Chemistry of Mammalian Metallothioneins

The Bioinorganic Chemistry of Mammalian Metallothioneins

Crosstalk of copper and zinc in the pathogenesis of vascular dementia

Effects of Zinc, Mercury, or Lead on [3H]MK-801 and [3H]Fluorowillardiine Binding to Rat Synaptic Membranes

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