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Zinc Signaling in Physiology and Pathogenesis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioinorganic Chemistry".

Deadline for manuscript submissions: closed (30 September 2017) | Viewed by 161404

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Special Issue Editors

Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
Interests: zinc signaling; Slc39a/ZIP and Slc30a/ZnT zinc transporters; signal transduction; physiology; disease
Special Issues, Collections and Topics in MDPI journals
Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Interests: zinc transporter; zinc metabolism; cellular biochemistry; metal enzymes; metal biology; absorption of essential trace elements; nutrient deficiency (Fe, Zn, Cu)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The essential trace element zinc plays indispensable roles in multiple cellular processes. It regulates a great number of protein functions, including transcription factors, enzymes, adapters, and growth factors as a structural and/or catalytic factor. Recent studies have highlighted another function of zinc as an intra- and intercellular signaling mediator, which became recognized as the “zinc signal”. Indeed, zinc regulates cellular signaling pathways, which enable conversion of extracellular stimuli to intracellular signals, and controls various intracellular and extracellular events, and thus zinc mediates communication between cells. The zinc signal is essential for physiology, and its dysregulation causes a variety of diseases, such as diabetes, cancer, osteoarthritis, dermatitis, and dementia.

This Special Issue focuses on crucial roles of zinc signaling in biological processes in molecular and physiological basis, addressing the future directions and questions underlying this unique phenomenon. Because there is growing interest and attention in physiopathological contribution of zinc signal, we believe this Special Issue will provide very timely information on it and thus should appeal to a wide range of readers.

The International Society for Zinc Biology Conference 2017 (ISZB-2017, http://www.uclan.ac.uk/conference_events/iszb-meeting-zino-net.php) will be held at Cyprus in 18-22 June 2017. All attendees presenting a paper at this conference are welcome to submit a manuscript for publication (Deadline: 30 September 2017). For further information, please contact the Editorial Office ( or ).

Prof. Dr. Toshiyuki Fukada  (ISZB board member)
Assoc. Prof. Dr. Taiho Kambe (ISZB Secretary)
Guest Editors

Manuscript Submission Information

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Keywords

  • Zinc signal
  • Zinc biology
  • Zinc transporters
  • Metallothionein
  • receptors and channels
  • physiology
  • disease

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Published Papers (19 papers)

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Editorial

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3 pages, 146 KiB  
Editorial
Welcome to the World of Zinc Signaling
by Toshiyuki Fukada and Taiho Kambe
Int. J. Mol. Sci. 2018, 19(3), 785; https://doi.org/10.3390/ijms19030785 - 09 Mar 2018
Cited by 14 | Viewed by 3772
Abstract
Zinc, an essential trace element, plays indispensable roles in multiple cellular processes.[...] Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)

Research

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8079 KiB  
Article
ZnT3 Gene Deletion Reduces Colchicine-Induced Dentate Granule Cell Degeneration
by Bo Young Choi, Dae Ki Hong and Sang Won Suh
Int. J. Mol. Sci. 2017, 18(10), 2189; https://doi.org/10.3390/ijms18102189 - 19 Oct 2017
Cited by 12 | Viewed by 5041
Abstract
Our previous study demonstrated that colchicine-induced dentate granule cell death is caused by blocking axonal flow and the accumulation of intracellular zinc. Zinc is concentrated in the synaptic vesicles via zinc transporter 3 (ZnT3), which facilitates zinc transport from the cytosol [...] Read more.
Our previous study demonstrated that colchicine-induced dentate granule cell death is caused by blocking axonal flow and the accumulation of intracellular zinc. Zinc is concentrated in the synaptic vesicles via zinc transporter 3 (ZnT3), which facilitates zinc transport from the cytosol into the synaptic vesicles. The aim of the present study was to identify the role of ZnT3 gene deletion on colchicine-induced dentate granule cell death. The present study used young (3–5 months) mice of the wild-type (WT) or the ZnT3/ genotype. Colchicine (10 µg/kg) was injected into the hippocampus, and then brain sections were evaluated 12 or 24 h later. Cell death was evaluated by Fluoro-Jade B; oxidative stress was analyzed by 4-hydroxy-2-nonenal; and dendritic damage was detected by microtubule-associated protein 2. Zinc accumulation was detected by N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining. Here, we found that ZnT3/ reduced the number of degenerating cells after colchicine injection. The ZnT3/-mediated inhibition of cell death was accompanied by suppression of oxidative injury, dendritic damage and zinc accumulation. In addition, ZnT3/ mice showed more glutathione content than WT mice and inhibited neuronal glutathione depletion by colchicine. These findings suggest that increased neuronal glutathione by ZnT3 gene deletion prevents colchicine-induced dentate granule cell death. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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2927 KiB  
Article
Zinc Transporter 3 (ZnT3) in the Enteric Nervous System of the Porcine Ileum in Physiological Conditions and during Experimental Inflammation
by Sławomir Gonkowski, Maciej Rowniak and Joanna Wojtkiewicz
Int. J. Mol. Sci. 2017, 18(2), 338; https://doi.org/10.3390/ijms18020338 - 07 Feb 2017
Cited by 6 | Viewed by 4967
Abstract
Zinc transporter 3 (ZnT3) is a member of the solute-linked carrier 30 (SLC 30) zinc transporter family. It is closely linked to the nervous system, where it takes part in the transport of zinc ions from the cytoplasm to the synaptic vesicles. ZnT3 [...] Read more.
Zinc transporter 3 (ZnT3) is a member of the solute-linked carrier 30 (SLC 30) zinc transporter family. It is closely linked to the nervous system, where it takes part in the transport of zinc ions from the cytoplasm to the synaptic vesicles. ZnT3 has also been observed in the enteric nervous system (ENS), but its reactions in response to pathological factors remain unknown. This study, based on the triple immunofluorescence technique, describes changes in ZnT3-like immunoreactive (ZnT3-LI) enteric neurons in the porcine ileum, caused by chemically-induced inflammation. The inflammatory process led to a clear increase in the percentage of neurons immunoreactive to ZnT3 in all “kinds” of intramural enteric plexuses, i.e., myenteric (MP), outer submucous (OSP) and inner submucous (ISP) plexuses. Moreover, a wide range of other active substances was noted in ZnT3-LI neurons under physiological and pathological conditions, and changes in neurochemical characterisation of ZnT3+ cells in response to inflammation depended on the “kind” of enteric plexus. The obtained results show that ZnT3 is present in the ENS in a relatively numerous and diversified neuronal population, not only in physiological conditions, but also during inflammation. The reasons for the observed changes are not clear; they may be connected with the functions of zinc ions and their homeostasis disturbances in pathological processes. On the other hand, they may be due to adaptive and/or neuroprotective processes within the pathologically altered gastrointestinal tract. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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3710 KiB  
Article
Zinc as a Signal to Stimulate Red Blood Cell Formation in Fish
by Yen-Hua Chen, Jhe-Ruei Shiu, Chia-Ling Ho and Sen-Shyong Jeng
Int. J. Mol. Sci. 2017, 18(1), 138; https://doi.org/10.3390/ijms18010138 - 11 Jan 2017
Cited by 31 | Viewed by 6606
Abstract
The common carp can tolerate extremely low oxygen levels. These fish store zinc in a specific zinc-binding protein presented in digestive tract tissues, and under low oxygen, the stored zinc is released and used as a signal to stimulate erythropoiesis (red blood cell [...] Read more.
The common carp can tolerate extremely low oxygen levels. These fish store zinc in a specific zinc-binding protein presented in digestive tract tissues, and under low oxygen, the stored zinc is released and used as a signal to stimulate erythropoiesis (red blood cell formation). To determine whether the environmental supply of zinc to other fish species can serve as a signal to induce erythropoiesis as in the common carp, head kidney cells of four different fish species were cultured with supplemental ZnCl2. Zinc stimulated approximately a three-fold increase in immature red blood cells (RBCs) in one day. The stimulation of erythropoiesis by zinc was dose-dependent. ZnSO4 solution was injected into an experimental blood loss tilapia model. Blood analysis and microscopic observation of the blood cells indicated that, in vivo, the presence of additional zinc induced erythropoiesis in the bled tilapia. In the fish species studied, zinc could be used as a signal to stimulate erythropoiesis both in vitro and in vivo. The present report suggests a possible approach for the induction of red blood cell formation in animals through the supply of a certain level of zinc through either diet or injection. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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2365 KiB  
Article
Zinc Up-Regulates Insulin Secretion from β Cell-Like Cells Derived from Stem Cells from Human Exfoliated Deciduous Tooth (SHED)
by Gyuyoup Kim, Ki-Hyuk Shin and Eung-Kwon Pae
Int. J. Mol. Sci. 2016, 17(12), 2092; https://doi.org/10.3390/ijms17122092 - 13 Dec 2016
Cited by 11 | Viewed by 5650
Abstract
Stem cells from human exfoliated deciduous tooth (SHED) offer several advantages over other stem cell sources. Using SHED, we examined the roles of zinc and the zinc uptake transporter ZIP8 (Zrt- and irt-like protein 8) while inducing SHED into insulin secreting β cell-like [...] Read more.
Stem cells from human exfoliated deciduous tooth (SHED) offer several advantages over other stem cell sources. Using SHED, we examined the roles of zinc and the zinc uptake transporter ZIP8 (Zrt- and irt-like protein 8) while inducing SHED into insulin secreting β cell-like stem cells (i.e., SHED-β cells). We observed that ZIP8 expression increased as SHED differentiated into SHED-β cells, and that zinc supplementation at day 10 increased the levels of most pancreatic β cell markers—particularly Insulin and glucose transporter 2 (GLUT2). We confirmed that SHED-β cells produce insulin successfully. In addition, we note that zinc supplementation significantly increases insulin secretion with a significant elevation of ZIP8 transporters in SHED-β cells. We conclude that SHED can be converted into insulin-secreting β cell-like cells as zinc concentration in the cytosol is elevated. Insulin production by SHED-β cells can be regulated via modulation of zinc concentration in the media as ZIP8 expression in the SHED-β cells increases. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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Review

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14 pages, 1113 KiB  
Review
Role of Zinc Homeostasis in the Pathogenesis of Diabetes and Obesity
by Ayako Fukunaka and Yoshio Fujitani
Int. J. Mol. Sci. 2018, 19(2), 476; https://doi.org/10.3390/ijms19020476 - 06 Feb 2018
Cited by 164 | Viewed by 16952
Abstract
Zinc deficiency is a risk factor for obesity and diabetes. However, until recently, the underlying molecular mechanisms remained unclear. The breakthrough discovery that the common polymorphism in zinc transporter SLC30A8/ZnT8 may increase susceptibility to type 2 diabetes provided novel insights into the [...] Read more.
Zinc deficiency is a risk factor for obesity and diabetes. However, until recently, the underlying molecular mechanisms remained unclear. The breakthrough discovery that the common polymorphism in zinc transporter SLC30A8/ZnT8 may increase susceptibility to type 2 diabetes provided novel insights into the role of zinc in diabetes. Our group and others showed that altered ZnT8 function may be involved in the pathogenesis of type 2 diabetes, indicating that the precise control of zinc homeostasis is crucial for maintaining health and preventing various diseases, including lifestyle-associated diseases. Recently, the role of the zinc transporter ZIP13 in the regulation of beige adipocyte biogenesis was clarified, which indicated zinc homeostasis regulation as a possible therapeutic target for obesity and metabolic syndrome. Here we review advances in the role of zinc homeostasis in the pathophysiology of diabetes, and propose that inadequate zinc distribution may affect the onset of diabetes and metabolic diseases by regulating various critical biological events. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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19 pages, 524 KiB  
Review
The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease
by Michal Hershfinkel
Int. J. Mol. Sci. 2018, 19(2), 439; https://doi.org/10.3390/ijms19020439 - 01 Feb 2018
Cited by 81 | Viewed by 9154
Abstract
A distinct G-protein coupled receptor that senses changes in extracellular Zn2+, ZnR/GPR39, was found in cells from tissues in which Zn2+ plays a physiological role. Most prominently, ZnR/GPR39 activity was described in prostate cancer, skin keratinocytes, and colon epithelial cells, [...] Read more.
A distinct G-protein coupled receptor that senses changes in extracellular Zn2+, ZnR/GPR39, was found in cells from tissues in which Zn2+ plays a physiological role. Most prominently, ZnR/GPR39 activity was described in prostate cancer, skin keratinocytes, and colon epithelial cells, where zinc is essential for cell growth, wound closure, and barrier formation. ZnR/GPR39 activity was also described in neurons that are postsynaptic to vesicular Zn2+ release. Activation of ZnR/GPR39 triggers Gαq-dependent signaling and subsequent cellular pathways associated with cell growth and survival. Furthermore, ZnR/GPR39 was shown to regulate the activity of ion transport mechanisms that are essential for the physiological function of epithelial and neuronal cells. Thus, ZnR/GPR39 provides a unique target for therapeutically modifying the actions of zinc in a specific and selective manner. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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1192 KiB  
Review
Recent Advances in the Role of SLC39A/ZIP Zinc Transporters In Vivo
by Teruhisa Takagishi, Takafumi Hara and Toshiyuki Fukada
Int. J. Mol. Sci. 2017, 18(12), 2708; https://doi.org/10.3390/ijms18122708 - 13 Dec 2017
Cited by 60 | Viewed by 8786
Abstract
Zinc (Zn), which is an essential trace element, is involved in numerous mammalian physiological events; therefore, either a deficiency or excess of Zn impairs cellular machineries and influences physiological events, such as systemic growth, bone homeostasis, skin formation, immune responses, endocrine function, and [...] Read more.
Zinc (Zn), which is an essential trace element, is involved in numerous mammalian physiological events; therefore, either a deficiency or excess of Zn impairs cellular machineries and influences physiological events, such as systemic growth, bone homeostasis, skin formation, immune responses, endocrine function, and neuronal function. Zn transporters are thought to mainly contribute to Zn homeostasis within cells and in the whole body. Recent genetic, cellular, and molecular studies of Zn transporters highlight the dynamic role of Zn as a signaling mediator linking several cellular events and signaling pathways. Dysfunction in Zn transporters causes various diseases. This review aims to provide an update of Zn transporters and Zn signaling studies and discusses the remaining questions and future directions by focusing on recent progress in determining the roles of SLC39A/ZIP family members in vivo. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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212 KiB  
Review
Zinc Signal in Brain Diseases
by Stuart D. Portbury and Paul A. Adlard
Int. J. Mol. Sci. 2017, 18(12), 2506; https://doi.org/10.3390/ijms18122506 - 23 Nov 2017
Cited by 108 | Viewed by 8273
Abstract
The divalent cation zinc is an integral requirement for optimal cellular processes, whereby it contributes to the function of over 300 enzymes, regulates intracellular signal transduction, and contributes to efficient synaptic transmission in the central nervous system. Given the critical role of zinc [...] Read more.
The divalent cation zinc is an integral requirement for optimal cellular processes, whereby it contributes to the function of over 300 enzymes, regulates intracellular signal transduction, and contributes to efficient synaptic transmission in the central nervous system. Given the critical role of zinc in a breadth of cellular processes, its cellular distribution and local tissue level concentrations remain tightly regulated via a series of proteins, primarily including zinc transporter and zinc import proteins. A loss of function of these regulatory pathways, or dietary alterations that result in a change in zinc homeostasis in the brain, can all lead to a myriad of pathological conditions with both acute and chronic effects on function. This review aims to highlight the role of zinc signaling in the central nervous system, where it may precipitate or potentiate diverse issues such as age-related cognitive decline, depression, Alzheimer’s disease or negative outcomes following brain injury. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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1285 KiB  
Review
The Impact of Synaptic Zn2+ Dynamics on Cognition and Its Decline
by Atsushi Takeda and Hanuna Tamano
Int. J. Mol. Sci. 2017, 18(11), 2411; https://doi.org/10.3390/ijms18112411 - 14 Nov 2017
Cited by 29 | Viewed by 3680
Abstract
The basal levels of extracellular Zn2+ are in the range of low nanomolar concentrations and less attention has been paid to Zn2+, compared to Ca2+, for synaptic activity. However, extracellular Zn2+ is necessary for synaptic activity. The [...] Read more.
The basal levels of extracellular Zn2+ are in the range of low nanomolar concentrations and less attention has been paid to Zn2+, compared to Ca2+, for synaptic activity. However, extracellular Zn2+ is necessary for synaptic activity. The basal levels of extracellular zinc are age-dependently increased in the rat hippocampus, implying that the basal levels of extracellular Zn2+ are also increased age-dependently and that extracellular Zn2+ dynamics are linked with age-related cognitive function and dysfunction. In the hippocampus, the influx of extracellular Zn2+ into postsynaptic neurons, which is often linked with Zn2+ release from neuron terminals, is critical for cognitive activity via long-term potentiation (LTP). In contrast, the excess influx of extracellular Zn2+ into postsynaptic neurons induces cognitive decline. Interestingly, the excess influx of extracellular Zn2+ more readily occurs in aged dentate granule cells and intracellular Zn2+-buffering, which is assessed with ZnAF-2DA, is weakened in the aged dentate granule cells. Characteristics (easiness) of extracellular Zn2+ influx seem to be linked with the weakened intracellular Zn2+-buffering in the aged dentate gyrus. This paper deals with the impact of synaptic Zn2+ signaling on cognition and its decline in comparison with synaptic Ca2+ signaling. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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1110 KiB  
Review
Impact of Labile Zinc on Heart Function: From Physiology to Pathophysiology
by Belma Turan and Erkan Tuncay
Int. J. Mol. Sci. 2017, 18(11), 2395; https://doi.org/10.3390/ijms18112395 - 12 Nov 2017
Cited by 30 | Viewed by 5277
Abstract
Zinc plays an important role in biological systems as bound and histochemically reactive labile Zn2+. Although Zn2+ concentration is in the nM range in cardiomyocytes at rest and increases dramatically under stimulation, very little is known about precise mechanisms controlling [...] Read more.
Zinc plays an important role in biological systems as bound and histochemically reactive labile Zn2+. Although Zn2+ concentration is in the nM range in cardiomyocytes at rest and increases dramatically under stimulation, very little is known about precise mechanisms controlling the intracellular distribution of Zn2+ and its variations during cardiac function. Recent studies are focused on molecular and cellular aspects of labile Zn2+ and its homeostasis in mammalian cells and growing evidence clarified the molecular mechanisms underlying Zn2+-diverse functions in the heart, leading to the discovery of novel physiological functions of labile Zn2+ in parallel to the discovery of subcellular localization of Zn2+-transporters in cardiomyocytes. Additionally, important experimental data suggest a central role of intracellular labile Zn2+ in excitation-contraction coupling in cardiomyocytes by shaping Ca2+ dynamics. Cellular labile Zn2+ is tightly regulated against its adverse effects through either Zn2+-transporters, Zn2+-binding molecules or Zn2+-sensors, and, therefore plays a critical role in cellular signaling pathways. The present review summarizes the current understanding of the physiological role of cellular labile Zn2+ distribution in cardiomyocytes and how a remodeling of cellular Zn2+-homeostasis can be important in proper cell function with Zn2+-transporters under hyperglycemia. We also emphasize the recent investigations on Zn2+-transporter functions from the standpoint of human heart health to diseases together with their clinical interest as target proteins in the heart under pathological condition, such as diabetes. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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2373 KiB  
Review
Elemental Ingredients in the Macrophage Cocktail: Role of ZIP8 in Host Response to Mycobacterium tuberculosis
by Charlie J. Pyle, Abul K. Azad, Audrey C. Papp, Wolfgang Sadee, Daren L. Knoell and Larry S. Schlesinger
Int. J. Mol. Sci. 2017, 18(11), 2375; https://doi.org/10.3390/ijms18112375 - 09 Nov 2017
Cited by 22 | Viewed by 6969
Abstract
Tuberculosis (TB) is a global epidemic caused by the infection of human macrophages with the world’s most deadly single bacterial pathogen, Mycobacterium tuberculosis (M.tb). M.tb resides in a phagosomal niche within macrophages, where trace element concentrations impact the immune response, bacterial [...] Read more.
Tuberculosis (TB) is a global epidemic caused by the infection of human macrophages with the world’s most deadly single bacterial pathogen, Mycobacterium tuberculosis (M.tb). M.tb resides in a phagosomal niche within macrophages, where trace element concentrations impact the immune response, bacterial metal metabolism, and bacterial survival. The manipulation of micronutrients is a critical mechanism of host defense against infection. In particular, the human zinc transporter Zrt-/Irt-like protein 8 (ZIP8), one of 14 ZIP family members, is important in the flux of divalent cations, including zinc, into the cytoplasm of macrophages. It also has been observed to exist on the membrane of cellular organelles, where it can serve as an efflux pump that transports zinc into the cytosol. ZIP8 is highly inducible in response to M.tb infection of macrophages, and we have observed its localization to the M.tb phagosome. The expression, localization, and function of ZIP8 and other divalent cation transporters within macrophages have important implications for TB prevention and dissemination and warrant further study. In particular, given the importance of zinc as an essential nutrient required for humans and M.tb, it is not yet clear whether ZIP-guided zinc transport serves as a host protective factor or, rather, is targeted by M.tb to enable its phagosomal survival. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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419 KiB  
Review
Dietary Zinc Acts as a Sleep Modulator
by Yoan Cherasse and Yoshihiro Urade
Int. J. Mol. Sci. 2017, 18(11), 2334; https://doi.org/10.3390/ijms18112334 - 05 Nov 2017
Cited by 59 | Viewed by 17486
Abstract
While zinc is known to be important for many biological processes in animals at a molecular and physiological level, new evidence indicates that it may also be involved in the regulation of sleep. Recent research has concluded that zinc serum concentration varies with [...] Read more.
While zinc is known to be important for many biological processes in animals at a molecular and physiological level, new evidence indicates that it may also be involved in the regulation of sleep. Recent research has concluded that zinc serum concentration varies with the amount of sleep, while orally administered zinc increases the amount and the quality of sleep in mice and humans. In this review, we provide an exhaustive study of the literature connecting zinc and sleep, and try to evaluate which molecular mechanism is likely to be involved in this phenomenon. A better understanding should provide critical information not only about the way zinc is related to sleep but also about how sleep itself works and what its real function is. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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966 KiB  
Review
Zinc in Cellular Regulation: The Nature and Significance of “Zinc Signals”
by Wolfgang Maret
Int. J. Mol. Sci. 2017, 18(11), 2285; https://doi.org/10.3390/ijms18112285 - 31 Oct 2017
Cited by 251 | Viewed by 10871
Abstract
In the last decade, we witnessed discoveries that established Zn2+ as a second major signalling metal ion in the transmission of information within cells and in communication between cells. Together with Ca2+ and Mg2+, Zn2+ covers biological regulation [...] Read more.
In the last decade, we witnessed discoveries that established Zn2+ as a second major signalling metal ion in the transmission of information within cells and in communication between cells. Together with Ca2+ and Mg2+, Zn2+ covers biological regulation with redox-inert metal ions over many orders of magnitude in concentrations. The regulatory functions of zinc ions, together with their functions as a cofactor in about three thousand zinc metalloproteins, impact virtually all aspects of cell biology. This article attempts to define the regulatory functions of zinc ions, and focuses on the nature of zinc signals and zinc signalling in pathways where zinc ions are either extracellular stimuli or intracellular messengers. These pathways interact with Ca2+, redox, and phosphorylation signalling. The regulatory functions of zinc require a complex system of precise homeostatic control for transients, subcellular distribution and traffic, organellar homeostasis, and vesicular storage and exocytosis of zinc ions. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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1372 KiB  
Review
Zinc Signals and Immunity
by Martina Maywald, Inga Wessels and Lothar Rink
Int. J. Mol. Sci. 2017, 18(10), 2222; https://doi.org/10.3390/ijms18102222 - 24 Oct 2017
Cited by 180 | Viewed by 17078
Abstract
Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. [...] Read more.
Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells. Main underlying molecular mechanisms and targets affected by altered zinc homeostasis, including kinases, caspases, phosphatases, and phosphodiesterases, will be highlighted in this article. In addition, the interplay of zinc homeostasis and the redox metabolism in affecting intracellular signaling will be emphasized. Key signaling pathways will be described in detail for the different cell types of the immune system. In this, effects of fast zinc flux, taking place within a few seconds to minutes will be distinguish from slower types of zinc signals, also designated as “zinc waves”, and late homeostatic zinc signals regarding prolonged changes in intracellular zinc. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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1259 KiB  
Review
Metallothioneins: Emerging Modulators in Immunity and Infection
by Kavitha Subramanian Vignesh and George S. Deepe Jr.
Int. J. Mol. Sci. 2017, 18(10), 2197; https://doi.org/10.3390/ijms18102197 - 23 Oct 2017
Cited by 145 | Viewed by 13635
Abstract
Metallothioneins (MTs) are a family of metal-binding proteins virtually expressed in all organisms including prokaryotes, lower eukaryotes, invertebrates and mammals. These proteins regulate homeostasis of zinc (Zn) and copper (Cu), mitigate heavy metal poisoning, and alleviate superoxide stress. In recent years, MTs have [...] Read more.
Metallothioneins (MTs) are a family of metal-binding proteins virtually expressed in all organisms including prokaryotes, lower eukaryotes, invertebrates and mammals. These proteins regulate homeostasis of zinc (Zn) and copper (Cu), mitigate heavy metal poisoning, and alleviate superoxide stress. In recent years, MTs have emerged as an important, yet largely underappreciated, component of the immune system. Innate and adaptive immune cells regulate MTs in response to stress stimuli, cytokine signals and microbial challenge. Modulation of MTs in these cells in turn regulates metal ion release, transport and distribution, cellular redox status, enzyme function and cell signaling. While it is well established that the host strictly regulates availability of metal ions during microbial pathogenesis, we are only recently beginning to unravel the interplay between metal-regulatory pathways and immunological defenses. In this perspective, investigation of mechanisms that leverage the potential of MTs to orchestrate inflammatory responses and antimicrobial defenses has gained momentum. The purpose of this review, therefore, is to illumine the role of MTs in immune regulation. We discuss the mechanisms of MT induction and signaling in immune cells and explore the therapeutic potential of the MT-Zn axis in bolstering immune defenses against pathogens. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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7871 KiB  
Review
Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway
by Taiho Kambe, Mayu Matsunaga and Taka-aki Takeda
Int. J. Mol. Sci. 2017, 18(10), 2179; https://doi.org/10.3390/ijms18102179 - 19 Oct 2017
Cited by 50 | Viewed by 7987
Abstract
More than one-third of newly synthesized proteins are targeted to the early secretory pathway, which is comprised of the endoplasmic reticulum (ER), Golgi apparatus, and other intermediate compartments. The early secretory pathway plays a key role in controlling the folding, assembly, maturation, modification, [...] Read more.
More than one-third of newly synthesized proteins are targeted to the early secretory pathway, which is comprised of the endoplasmic reticulum (ER), Golgi apparatus, and other intermediate compartments. The early secretory pathway plays a key role in controlling the folding, assembly, maturation, modification, trafficking, and degradation of such proteins. A considerable proportion of the secretome requires zinc as an essential factor for its structural and catalytic functions, and recent findings reveal that zinc plays a pivotal role in the function of the early secretory pathway. Hence, a disruption of zinc homeostasis and metabolism involving the early secretory pathway will lead to pathway dysregulation, resulting in various defects, including an exacerbation of homeostatic ER stress. The accumulated evidence indicates that specific members of the family of Zn transporters (ZNTs) and Zrt- and Irt-like proteins (ZIPs), which operate in the early secretory pathway, play indispensable roles in maintaining zinc homeostasis by regulating the influx and efflux of zinc. In this review, the biological functions of these transporters are discussed, focusing on recent aspects of their roles. In particular, we discuss in depth how specific ZNT transporters are employed in the activation of zinc-requiring ectoenzymes. The means by which early secretory pathway functions are controlled by zinc, mediated by specific ZNT and ZIP transporters, are also subjects of this review. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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Discussion
Pan-Domain Analysis of ZIP Zinc Transporters
by Laura E. Lehtovirta-Morley, Mohammad Alsarraf and Duncan Wilson
Int. J. Mol. Sci. 2017, 18(12), 2631; https://doi.org/10.3390/ijms18122631 - 06 Dec 2017
Cited by 14 | Viewed by 4480
Abstract
The ZIP (Zrt/Irt-like protein) family of zinc transporters is found in all three domains of life. However, little is known about the phylogenetic relationship amongst ZIP transporters, their distribution, or their origin. Here we employed phylogenetic analysis to explore the evolution of ZIP [...] Read more.
The ZIP (Zrt/Irt-like protein) family of zinc transporters is found in all three domains of life. However, little is known about the phylogenetic relationship amongst ZIP transporters, their distribution, or their origin. Here we employed phylogenetic analysis to explore the evolution of ZIP transporters, with a focus on the major human fungal pathogen, Candida albicans. Pan-domain analysis of bacterial, archaeal, fungal, and human proteins revealed a complex relationship amongst the ZIP family members. Here we report (i) a eukaryote-wide group of cellular zinc importers, (ii) a fungal-specific group of zinc importers having genetic association with the fungal zincophore, and, (iii) a pan-kingdom supercluster made up of two distinct subgroups with orthologues in bacterial, archaeal, and eukaryotic phyla. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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Conference Report
Report of the International Society for Zinc Biology 5th Meeting, in Collaboration with Zinc-Net (COST Action TD1304)—UCLan Campus, Pyla, Cyprus
by Nicola M. Lowe and Victoria Hall Moran
Int. J. Mol. Sci. 2017, 18(12), 2518; https://doi.org/10.3390/ijms18122518 - 24 Nov 2017
Cited by 2 | Viewed by 3147
Abstract
From 18 to 22 June 2017, the fifth biennial meeting of the International Society for Zinc Biology was held in conjunction with the final dissemination meeting of the Network for the Biology of Zinc (Zinc-Net) at the University of Central Lancashire, Cyprus campus. [...] Read more.
From 18 to 22 June 2017, the fifth biennial meeting of the International Society for Zinc Biology was held in conjunction with the final dissemination meeting of the Network for the Biology of Zinc (Zinc-Net) at the University of Central Lancashire, Cyprus campus. The meeting attracted over 160 participants, had 17 scientific symposia, 4 plenary speakers and 2 poster discussion sessions. In this report, we give an overview of the key themes of the meeting and some of the highlights from the scientific programme. Full article
(This article belongs to the Special Issue Zinc Signaling in Physiology and Pathogenesis)
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