Zinc is a novel intracellular second messenger

Yamasaki, Satoshi; Sakata‐Sogawa, Kumiko; Hasegawa, Aiko; Suzuki, Tomoyuki; Kabu, Koki; Sato, Eriko; Kurosaki, Tomohiro; Yamashita, Susumu; Tokunaga, Makio; Nishida, Keigo; Hirano, Toshio

doi:10.1083/jcb.200702081

Cited by 522 publications

(482 citation statements)

References 56 publications

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“…It is unknown the concentration range of cellular zinc that is needed for cypin's effect on dendrite branching. But interestingly, it was previously reported that zinc is released from the perinuclear area, including the endoplasmic reticulum, in mast cells in response to stimulation and can act as a second messenger 21 ; however, it is unknown whether this occurs in neurons and whether this pool of zinc can activate cypin and promote dendrite branching.…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of the zinc binding domain in cytosolic PSD‐95 interactor (cypin): Role of zinc binding in guanine deamination and dendrite branching

Fernández

Welsh²,

Firestein

2008

Proteins

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Dendrite morphology regulates how a postsynaptic neuron receives information from presynaptic neurons. The specific patterning of dendrite branches is promoted by extrinsic and intrinsic factors that trigger the activation of functional signaling pathways. However, most of the regulating factors and the biochemical mechanisms involved in regulating dendrite branching are unknown. Our laboratory previously reported that cypin (cytosolic PSD-95 interactor) plays an active role in regulating dendrite branching in hippocampal neurons. Cypin-promoted increases in dendrite number are dependent on guanine deaminase activity. In order to identify the specific structural role of zincbinding in cypin-mediated dendrite branching and guanine deaminase activity, we employed computational homology modeling techniques to construct a three dimensional structural model of cypin. Analysis of the protein-ion sequestration scaffold of this model identified several histidines and aspartic acid residues responsible for zinc binding. Single substitution mutations in these specific sites completely disrupted the guanine deaminase enzymatic activity and rendered cypin unable to promote dendrite branching in rat hippocampal neurons. The specific zinc ion-binding function of each residue in the protein scaffold was also confirmed by Inductively Coupled Plasma-Optic Emission Spectrometry. Inspection of our structural model confirmed that His82 and His84 coordinate with the zinc ion, together with His240, His279, and Asp330, residues that until now were unknown to play a role in this regard. Furthermore, promotion of dendrite branching by cypin is zincdependent.

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Section: Discussionmentioning

confidence: 99%

Structural characterization of the zinc binding domain in cytosolic PSD‐95 interactor (cypin): Role of zinc binding in guanine deamination and dendrite branching

Fernández

Welsh²,

Firestein

2008

Proteins

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“…In the above experiments, Zn 2 + was absent from the extracellular buffer, suggesting that Zn 2 + release occurred from an intracellular source. To exclude the contribution of any contaminating Zn 2 + , we have included the cell-impermeable Zn 2 + chelator, DTPA [30], in the extracellular buffer. DTPA failed to prevent the H 2 O 2 -induced Zn 2 + response; by contrast, the cell-permeable Zn 2 + chelator, TPEN, completely prevented the Zn 2 + response (Figures 2A and 2B).…”

Section: The Source Of Trpm2-targeted Zn 2 + Stores Is Intracellularmentioning

confidence: 99%

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Manna

Munsey

Abuarab

et al. 2015

Biochemical Journal

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Reactive oxygen species (ROS) can cause pancreatic β-cell death by activating transient receptor potential (melastatin) 2 (TRPM2) channels. Cell death has been attributed to the ability of these channels to raise cytosolic Ca 2 + . Recent studies however revealed that TRPM2 channels can also conduct Zn 2 + , but the physiological relevance of this property is enigmatic. Given that Zn 2 + is cytotoxic, we asked whether TRPM2 channels can permeate sufficient Zn 2 + to affect cell viability. To address this, we used the insulin secreting (INS1) β-cell line, human embryonic kidney (HEK)-293 cells transfected with TRPM2 and pancreatic islets. H 2 O 2 activation of TRPM2 channels increases the cytosolic levels of both Ca 2 + and Zn 2 + and causes apoptotic cell death. Interestingly, chelation of Zn 2 + alone was sufficient to prevent β-cell death. The source of the cytotoxic Zn 2 + is intracellular, found largely sequestered in lysosomes. Lysosomes express TRPM2 channels, providing a potential route for Zn 2 + release. Zn 2 + release is potentiated by extracellular Ca 2 + entry, indicating that Ca 2 + -induced Zn 2 + release leads to apoptosis. Knockout of TRPM2 channels protects mice from β-cell death and hyperglycaemia induced by multiple low-dose streptozotocin (STZ; MLDS) administration. These results argue that TRPM2-mediated, Ca 2 + -potentiated Zn 2 + release underlies ROS-induced β-cell death and Zn 2 + , rather than Ca 2 + , plays a primary role in apoptosis.

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“…Zinc modulates the activity of proteins such as receptors and enzymes that are involved in the regulation of numerous processes, including the synthesis of macromolecules, the regulation of signaling cascades and gene transcription, and transport processes. In this capacity, a role for zinc as a second messenger of intracellular signal transduction has recently been recognized (Yamasaki et al 2007). Zinc is also involved in preserving genomic stability through several actions including regulation of redox homeostasis [reviewed in (Oteiza 2012)], DNA repair, synthesis, and methylation (Sharif et al 2012).…”

Section: Biological Functions Of Zincmentioning

confidence: 99%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

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Zinc is a novel intracellular second messenger

Cited by 522 publications

References 56 publications

Structural characterization of the zinc binding domain in cytosolic PSD‐95 interactor (cypin): Role of zinc binding in guanine deamination and dendrite branching

Structural characterization of the zinc binding domain in cytosolic PSD‐95 interactor (cypin): Role of zinc binding in guanine deamination and dendrite branching

TRPM2-mediated intracellular Zn2+ release triggers pancreatic β-cell death

Zinc and the aging brain

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