Modulation of Neuronal Signal Transduction and Memory Formation by Synaptic Zinc

Sindreu, Carlos; Storm, Daniel R.

doi:10.3389/fnbeh.2011.00068

Cited by 57 publications

(49 citation statements)

References 188 publications

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“…Although intracellular concentrations of free zinc are low (<1 nM) (12), zinc is accumulated at high levels in various stores, such as the endoplasmic reticulum, mitochondria, and synaptic vesicles. In the synaptic vesicles, the concentrations of free zinc could reach the millimolar level (13). During synaptic transmission vesicular zinc is released, and quantities of zinc translocate to the postsynaptic terminals through zinc-permeable channels such as AMPA receptors (14).…”

mentioning

confidence: 99%

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

Gao

Boillat

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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M-type (Kv7, KCNQ) potassium channels are proteins that control the excitability of neurons and muscle cells. Many physiological and pathological mechanisms of excitation operate via the suppression of M channel activity or expression. Conversely, pharmacological augmentation of M channel activity is a recognized strategy for the treatment of hyperexcitability disorders such as pain and epilepsy. However, physiological mechanisms resulting in M channel potentiation are rare. Here we report that intracellular free zinc directly and reversibly augments the activity of recombinant and native M channels. This effect is mechanistically distinct from the known redoxdependent KCNQ channel potentiation. Interestingly, the effect of zinc cannot be attributed to a single histidine-or cysteine-containing zinc-binding site within KCNQ channels. Instead, zinc dramatically reduces KCNQ channel dependence on its obligatory physiological activator, phosphatidylinositol 4,5-bisphosphate (PIP 2 ). We hypothesize that zinc facilitates interactions of the lipid-facing interface of a KCNQ protein with the inner leaflet of the plasma membrane in a way similar to that promoted by PIP 2 . Because zinc is increasingly recognized as a ubiquitous intracellular second messenger, this discovery might represent a hitherto unknown native pathway of M channel modulation and provide a fresh strategy for the design of M channel activators for therapeutic purposes.+ channels are a family of voltagegated K + channels with a very distinctive and robust role in the control of cellular excitability. The channels give rise to noninactivating K + currents with slow kinetics and a very negative activation threshold (−60 mV or even more negative). In combination, these features allow KCNQ channels to remain partially active at voltages near the resting membrane potential of a neuron or a muscle cell and thus strongly influence excitability (1, 2). Transient KCNQ channel inhibition leads to reversible increases in neuronal excitability, whereas long-term losses of KCNQ channel activity often result in debilitating excitability disorders (1, 2). Thus, loss-of-function mutations within KCNQ genes underlie some types of epilepsy, deafness, and arrhythmias, whereas transcriptional down-regulation in sensory nerves may result in chronic pain (2). Conversely, M channel enhancers ("openers") reduce excitability and are clinically used as antiepileptic drugs (e.g., retigabine) or analgesics (e.g., flupirtine) (3). The therapeutic utility of KCNQ channel openers extends to other disorders linked to deregulated excitability, such as anxiety, stroke, and smooth muscle disorders (2, 3); therefore a global quest for specific and selective KCNQ openers is currently underway (3).The KCNQ channel family contains five members, KCNQ1-5 (Kv7.1-Kv7.5). KCNQ1 is expressed mostly within the cardiovascular system, whereas the other members are predominantly neuronal (1, 2). The most abundant M-type channel within the nervous system is believed to be the heteromeric KCNQ2/3 chan...

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confidence: 99%

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

Gao

Boillat

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Although, further studies are required to elucidate this hypothesis, a small amount of reactive Zn in the zebrafish telencephalon could be sufficient to perform an allosteric modulation, like in mammals. 50,51 It is well known that the abundant reactive Zn stained by Neo-Timm in the rodent hippocampus is associated with learning and memory formation 5 because Zn acts as a neuromodulator colocalized in vesicles with glutamate in Zncontaining neurons. 3 In fact, the corelease of reactive Zn and glutamate has been observed at the synaptic terminals of rod photoreceptors in zebrafish, modulating the synaptic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Zn is an important neuromodulator at synapses of specific brain regions, for example, the hippocampus and cortex, 3,4 and it is implicated in the memory formation process. 5 Alterations in Zn levels contribute to the imbalance in neurotransmission 6 and brain hypoxia 7 that is associated with brain disorders such as seizures and neuronal injury, respectively. Thus, the cellular control of Zn levels in the central nervous system (CNS) is critical for its homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Topographical Analysis of Reactive Zinc in the Central Nervous System of Adult Zebrafish (Danio Rerio)

Braga

Oliveira²,

Loss³

et al. 2013

Zebrafish

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Reactive zinc (Zn) is crucial for neuronal signaling and is largely distributed within presynaptic vesicles of some axon terminals of distinct vertebrates. However, the distribution of reactive Zn throughout the central nervous system (CNS) is not fully explored. We performed a topographical study of CNS structures containing reactive Zn in the adult zebrafish (Danio rerio). Slices of CNS from zebrafish were stained by Neo-Timm and/or cresyl violet. The Zn specificity of Neo-Timm was evaluated with Zn chelants, N,N,N¢,N¢-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), sodium diethyldithiocarbamate (DEDTC), Zn sulfide washing solution, and hydrochloric acid (HCl). Unfixed slices were also immersed in the fluorescent Zn probe (zinpyr-1). Yellowto-brown-to-black granules were revealed by Neo-Timm in the zebrafish CNS. Telencephalon exhibited slightly stained regions, while rhombencephalic structures showed high levels of staining. Although stained granules were found on the cell bodies, rhombencephalic structures showed a neuropil staining profile. The TPEN produced a mild reduction in Neo-Timm staining, while HCl and mainly DEDTC abolished the staining, indicating a large Zn content. This result was also confirmed by the application of a Zn probe. The present topographical study revealed reactive Zn throughout the CNS in adult zebrafish that should be considered in future investigation of Zn in the brain on a larger scale.

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“…A class of glutaminergic neurons store zinc in specific synaptic vesicles which is released as a neuro-modulator in an activity-dependent manner [18]. Synaptic plasticity indicates the presence of high zinc concentration at synapses which is critical for learning and memory [19]. The roles of zinc in central nervous system include: a, the involvement of zinc -dependent enzymes in brain growth; b, the participation of zincfinger proteins in brain structure and neurotransmission; c, the involvement of zinc -dependent neurotransmitters in brain memory function; d, the involvement of zinc in the precursor production of neurotransmitters; e, the role of metallothionein-III as a protein that binds zinc in neurons [20].…”

Section: Discussionmentioning

confidence: 99%

A Research on the Level of Zinc and Copper in the Hair of Students with Lower IQ

Meghrazi

Sabet²,

Kheradmand

et al. 2017

Zahedan J Res Med Sci

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Background: The measurement of trace elements in human body has proved to be of great use in the evaluation of human health and the diagnosis of various diseases. No light, however, has been shed on these elements where they concern the human intelligence. Objectives:The goal is to make a comparison between the students with a lower IQ and those having an ordinary IQ in terms of the amount of zinc and copper as two trace elements. Methods: This is a case-control study and the subjects as the patients were chosen from mentally retarded students having no particular diseases. The sample size for the patient and control was 30 for each. The hair samples of the experimental group and the ordinary students (the control group) were digested with concentrated HNO3 after being washed with water and acetone. After being digested, the values of zinc and copper in the samples were measured with atomic absorption spectroscopy. The obtained data were analyzed using SPSS-15 via two independent sample tests of significance tests.

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Modulation of Neuronal Signal Transduction and Memory Formation by Synaptic Zinc

Cited by 57 publications

References 188 publications

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

Intracellular zinc activates KCNQ channels by reducing their dependence on phosphatidylinositol 4,5-bisphosphate

Topographical Analysis of Reactive Zinc in the Central Nervous System of Adult Zebrafish (Danio Rerio)

A Research on the Level of Zinc and Copper in the Hair of Students with Lower IQ

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