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Special Issue "Calcium-Binding Proteins and Cell Signaling"

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

Deadline for manuscript submissions: closed (31 March 2019)

Special Issue Editors

Guest Editor
Prof. Dr. Masatoshi Maki

Department of Applied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
Website 1 | Website 2 | E-Mail
Interests: ion chennel; calcium-binding protein; calpain; cancer; protease; protein–protein interaction; protein structure; proteolysis; splicing; ubiquitination
Guest Editor
Assoc. Prof. Hideki Shibata

Department of Applied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
Website 1 | Website 2 | E-Mail
Interests: annexin; apoptosis; calcium signaling; EF-hand protein; ER-to-Golgi transport; endocytosis; endosome; lysosome; membrane trafficking; vesicular transport

Special Issue Information

Dear Colleagues,

Calcium ions play pivotal roles in a variety of cellular events including signal transduction, gene expression, cell death, fertilization, muscle contraction, membrane fusion, blood clotting, enzymatic activations of kinases, phosphatases, proteases, etc., by involving different kinds of calcium-binding proteins. The concentrations of Ca2+ in the blood and inside the cells are strictly regulated by Ca2+-sensor proteins, channels, transporters, and Ca2+-buffering proteins. In addition to the sarcoplasmic/endoplasmic reticulum known as the major Ca2+-storage organelle in the cell, mitochondria, Golgi apparatus, endosomes, and lysosomes are also known to play roles in Ca2+signaling. Nuclear roles of Ca2+ in transcriptional and post-transcriptional regulation also draw attention. Ca2+ works not only as a second messenger but also as a first messenger for Ca2+-sensing receptors located on the plasma membrane. Abnormalities in Ca2+ homeostasis or in functions of Ca2+-regulated factors cause, directly or indirectly, various diseases, such as neuropathies, heart failure, immune disorders, and osteogenesis imperfecta. Ca2+-dependent phenomena are not restricted to animals, but plants, lower eukaryotes, and some bacteria also use Ca2+ as a signaling molecule. This Special Issue on Calcium-Binding Proteins and Cell Signaling welcomes contributions in all areas of basic and application-oriented research associated with calcium on the aspects of biochemistry, cell biology, molecular biology, and biophysics.

Prof. Dr. Masatoshi Maki
Assoc. Prof. Hideki Shibata
Guest Editors

Manuscript Submission Information

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Keywords

  • EF-hand proteins
  • Annexin family
  • C2 domain proteins
  • Ion channels and transporters
  • Ca2+ sensors and Ca2+-buffering proteins
  • Ca2+-dependent enzymes (calcineurin, calpain, PKC, etc.)
  • Transcription factors (NFAT, TFEB, etc.)
  • Signal transduction
  • Cell growth, differentiation, and death
  • Membrane trafficking
  • Organellar Ca2+
  • Ca2+ assay methods

Published Papers (7 papers)

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Research

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Open AccessArticle
Changes of Thermostability, Organic Solvent, and pH Stability in Geobacillus zalihae HT1 and Its Mutant by Calcium Ion
Int. J. Mol. Sci. 2019, 20(10), 2561; https://doi.org/10.3390/ijms20102561
Received: 25 March 2019 / Revised: 23 April 2019 / Accepted: 30 April 2019 / Published: 24 May 2019
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Abstract
Thermostable T1 lipase from Geobacillus zalihae has been crystallized using counter-diffusion method under space and Earth conditions. The comparison of the three-dimensional structures from both crystallized proteins show differences in the formation of hydrogen bond and ion interactions. Hydrogen bond and ion interaction [...] Read more.
Thermostable T1 lipase from Geobacillus zalihae has been crystallized using counter-diffusion method under space and Earth conditions. The comparison of the three-dimensional structures from both crystallized proteins show differences in the formation of hydrogen bond and ion interactions. Hydrogen bond and ion interaction are important in the stabilization of protein structure towards extreme temperature and organic solvents. In this study, the differences of hydrogen bond interactions at position Asp43, Thr118, Glu250, and Asn304 and ion interaction at position Glu226 was chosen to imitate space-grown crystal structure, and the impact of these combined interactions in T1 lipase-mutated structure was studied. Using space-grown T1 lipase structure as a reference, subsequent simultaneous mutation D43E, T118N, E226D, E250L, and N304E was performed on recombinant wild-type T1 lipase (wt-HT1) to generate a quintuple mutant term as 5M mutant lipase. This mutant lipase shared similar characteristics to its wild-type in terms of optimal pH and temperature. The stability of mutant 5M lipase improved significantly in acidic and alkaline pH as compared to wt-HT1. 5M lipase was highly stable in organic solvents such as dimethyl sulfoxide (DMSO), methanol, and n-hexane compared to wt-HT1. Both wild-type and mutant lipases were found highly activated in calcium as compared to other metal ions due to the presence of calcium-binding site for thermostability. The presence of calcium prolonged the half-life of mutant 5M and wt-HT1, and at the same time increased their melting temperature (Tm). The melting temperature of 5M and wt-HT1 lipases increased at 8.4 and 12.1 °C, respectively, in the presence of calcium as compared to those without. Calcium enhanced the stability of mutant 5M in 25% (v/v) DMSO, n-hexane, and n-heptane. The lipase activity of wt-HT1 also increased in 25% (v/v) ethanol, methanol, acetonitrile, n-hexane, and n-heptane in the presence of calcium. The current study showed that the accumulation of amino acid substitutions D43E, T118N, E226D, E250L, and N304E produced highly stable T1 mutant when hydrolyzing oil in selected organic solvents such as DMSO, n-hexane, and n-heptane. It is also believed that calcium ion plays important role in regulating lipase thermostability. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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Open AccessArticle
Inhibition of Calcium/Calmodulin-Dependent Protein Kinase Kinase β Is Detrimental in Hypoxia–Ischemia Neonatal Brain Injury
Int. J. Mol. Sci. 2019, 20(9), 2063; https://doi.org/10.3390/ijms20092063
Received: 29 March 2019 / Revised: 16 April 2019 / Accepted: 24 April 2019 / Published: 26 April 2019
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Abstract
Neonatal hypoxia–ischemia (HI) is a major cause of death and disability in neonates. HI leads to a dramatic rise in intracellular calcium levels, which was originally thought to be detrimental to the brain. However, it has been increasingly recognized that this calcium signaling [...] Read more.
Neonatal hypoxia–ischemia (HI) is a major cause of death and disability in neonates. HI leads to a dramatic rise in intracellular calcium levels, which was originally thought to be detrimental to the brain. However, it has been increasingly recognized that this calcium signaling may also play an important protective role after injury by triggering endogenous neuroprotective pathways. Calcium/calmodulin-dependent protein kinase kinase β (CaMKK β) is a major kinase activated by elevated levels of intracellular calcium. Here we evaluated the functional role of CaMKK β in neonatal mice after HI in both acute and chronic survival experiments. Postnatal day ten wild-type (WT) and CaMKK β knockout (KO) mouse male pups were subjected to unilateral carotid artery ligation, followed by 40 min of hypoxia (10% O2 in N2). STO-609, a CaMKK inhibitor, was administered intraperitoneally to WT mice at 5 minutes after HI. TTC (2,3,5-triphenyltetrazolium chloride monohydrate) staining was used to assess infarct volume 24 h after HI. CaMKK β KO mice had larger infarct volume than WT mice and STO-609 increased the infarct volume in WT mice after HI. In chronic survival experiments, WT mice treated with STO-609 showed increased tissue loss in the ipsilateral hemisphere three weeks after HI. Furthermore, when compared with vehicle-treated mice, they showed poorer functional recovery during the three week survival period, as measured by the wire hang test and corner test. Loss of blood–brain barrier proteins, a reduction in survival protein (Bcl-2), and an increase in pro-apoptotic protein Bax were also seen after HI with CaMKK β inhibition. In conclusion, inhibition of CaMKK β exacerbated neonatal hypoxia–ischemia injury in mice. Our data suggests that enhancing CaMKK signaling could be a potential target for the treatment of hypoxic–ischemic brain injury. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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Open AccessArticle
Metabolic Inhibition Induces Transient Increase of L-type Ca2+ Current in Human and Rat Cardiac Myocytes
Int. J. Mol. Sci. 2019, 20(6), 1501; https://doi.org/10.3390/ijms20061501
Received: 19 February 2019 / Revised: 15 March 2019 / Accepted: 23 March 2019 / Published: 26 March 2019
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Abstract
Metabolic inhibition is a common condition observed during ischemic heart disease and heart failure. It is usually accompanied by a reduction in L-type Ca2+ channel (LTCC) activity. In this study, however, we show that metabolic inhibition results in a biphasic effect on [...] Read more.
Metabolic inhibition is a common condition observed during ischemic heart disease and heart failure. It is usually accompanied by a reduction in L-type Ca2+ channel (LTCC) activity. In this study, however, we show that metabolic inhibition results in a biphasic effect on LTCC current (ICaL) in human and rat cardiac myocytes: an initial increase of ICaL is observed in the early phase of metabolic inhibition which is followed by the more classical and strong inhibition. We studied the mechanism of the initial increase of ICaL in cardiac myocytes during β-adrenergic stimulation by isoprenaline, a non-selective agonist of β-adrenergic receptors. The whole-cell patch–clamp technique was used to record the ICaL in single cardiac myocytes. The initial increase of ICaL was induced by a wide range of metabolic inhibitors (FCCP, 2,4-DNP, rotenone, antimycin A). In rat cardiomyocytes, the initial increase of ICaL was eliminated when the cells were pre-treated with thapsigargin leading to the depletion of Ca2+ from the sarcoplasmic reticulum (SR). Similar results were obtained when Ca2+ release from the SR was blocked with ryanodine. These data suggest that the increase of ICaL in the early phase of metabolic inhibition is due to a reduced calcium dependent inactivation (CDI) of LTCCs. This was further confirmed in human atrial myocytes where FCCP failed to induce the initial stimulation of ICaL when Ca2+ was replaced by Ba2+, eliminating CDI of LTCCs. We conclude that the initial increase in ICaL observed during the metabolic inhibition in human and rat cardiomyocytes is a consequence of an acute reduction of Ca2+ release from SR resulting in reduced CDI of LTCCs. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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Graphical abstract

Open AccessArticle
Inhibition of Triple-Negative Breast Cancer Cell Aggressiveness by Cathepsin D Blockage: Role of Annexin A1
Int. J. Mol. Sci. 2019, 20(6), 1337; https://doi.org/10.3390/ijms20061337
Received: 26 February 2019 / Revised: 13 March 2019 / Accepted: 13 March 2019 / Published: 16 March 2019
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Abstract
Triple-negative breast cancers (TNBCs) are more aggressive than other breast cancer (BC) subtypes and lack effective therapeutic options. Unraveling marker events of TNBCs may provide new directions for development of strategies for targeted TNBC therapy. Herein, we reported that Annexin A1 (AnxA1) and [...] Read more.
Triple-negative breast cancers (TNBCs) are more aggressive than other breast cancer (BC) subtypes and lack effective therapeutic options. Unraveling marker events of TNBCs may provide new directions for development of strategies for targeted TNBC therapy. Herein, we reported that Annexin A1 (AnxA1) and Cathepsin D (CatD) are highly expressed in MDA-MB-231 (TNBC lineage), compared to MCF-10A and MCF-7. Since the proposed concept was that CatD has protumorigenic activity associated with its ability to cleave AnxA1 (generating a 35.5 KDa fragment), we investigated this mechanism more deeply using the inhibitor of CatD, Pepstatin A (PepA). Fourier Transform Infrared (FTIR) spectroscopy demonstrated that PepA inhibits CatD activity by occupying its active site; the OH bond from PepA interacts with a CO bond from carboxylic acids of CatD catalytic aspartate dyad, favoring the deprotonation of Asp33 and consequently inhibiting CatD. Treatment of MDA-MB-231 cells with PepA induced apoptosis and autophagy processes while reducing the proliferation, invasion, and migration. Finally, in silico molecular docking demonstrated that the catalytic inhibition comprises Asp231 protonated and Asp33 deprotonated, proving all functional results obtained. Our findings elucidated critical CatD activity in TNBC cell trough AnxA1 cleavage, indicating the inhibition of CatD as a possible strategy for TNBC treatment. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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Review

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Open AccessReview
Calcium-Binding Proteins in the Nervous System during Hibernation: Neuroprotective Strategies in Hypometabolic Conditions?
Int. J. Mol. Sci. 2019, 20(9), 2364; https://doi.org/10.3390/ijms20092364
Received: 14 April 2019 / Revised: 6 May 2019 / Accepted: 11 May 2019 / Published: 13 May 2019
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Abstract
Calcium-binding proteins (CBPs) can influence and react to Ca2+ transients and modulate the activity of proteins involved in both maintaining homeostatic conditions and protecting cells in harsh environmental conditions. Hibernation is a strategy that evolved in vertebrate and invertebrate species to survive [...] Read more.
Calcium-binding proteins (CBPs) can influence and react to Ca2+ transients and modulate the activity of proteins involved in both maintaining homeostatic conditions and protecting cells in harsh environmental conditions. Hibernation is a strategy that evolved in vertebrate and invertebrate species to survive in cold environments; it relies on molecular, cellular, and behavioral adaptations guided by the neuroendocrine system that together ensure unmatched tolerance to hypothermia, hypometabolism, and hypoxia. Therefore, hibernation is a useful model to study molecular neuroprotective adaptations to extreme conditions, and can reveal useful applications to human pathological conditions. In this review, we describe the known changes in Ca2+-signaling and the detection and activity of CBPs in the nervous system of vertebrate and invertebrate models during hibernation, focusing on cytosolic Ca2+ buffers and calmodulin. Then, we discuss these findings in the context of the neuroprotective and neural plasticity mechanisms in the central nervous system: in particular, those associated with cytoskeletal proteins. Finally, we compare the expression of CBPs in the hibernating nervous system with two different conditions of neurodegeneration, i.e., platinum-induced neurotoxicity and Alzheimer’s disease, to highlight the similarities and differences and demonstrate the potential of hibernation to shed light into part of the molecular mechanisms behind neurodegenerative diseases. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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Open AccessReview
Expression of Ca2+-Binding Buffer Proteins in the Human and Mouse Retinal Neurons
Int. J. Mol. Sci. 2019, 20(9), 2229; https://doi.org/10.3390/ijms20092229
Received: 12 April 2019 / Revised: 30 April 2019 / Accepted: 3 May 2019 / Published: 7 May 2019
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Abstract
Ca2+-binding buffer proteins (CaBPs) are widely expressed by various neurons throughout the central nervous system (CNS), including the retina. While the expression of CaBPs by photoreceptors, retinal interneurons and the output ganglion cells in the mammalian retina has been extensively studied, [...] Read more.
Ca2+-binding buffer proteins (CaBPs) are widely expressed by various neurons throughout the central nervous system (CNS), including the retina. While the expression of CaBPs by photoreceptors, retinal interneurons and the output ganglion cells in the mammalian retina has been extensively studied, a general description is still missing due to the differences between species, developmental expression patterns and study-to-study discrepancies. Furthermore, CaBPs are occasionally located in a compartment-specific manner and two or more CaBPs can be expressed by the same neuron, thereby sharing the labor of Ca2+ buffering in the intracellular milieu. This article reviews this topic by providing a framework on CaBP functional expression by neurons of the mammalian retina with an emphasis on human and mouse retinas and the three most abundant and extensively studied buffer proteins: parvalbumin, calretinin and calbindin. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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Open AccessReview
Calcium-Binding Proteins as Determinants of Central Nervous System Neuronal Vulnerability to Disease
Int. J. Mol. Sci. 2019, 20(9), 2146; https://doi.org/10.3390/ijms20092146
Received: 30 March 2019 / Revised: 26 April 2019 / Accepted: 27 April 2019 / Published: 30 April 2019
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Abstract
Neuronal subpopulations display differential vulnerabilities to disease, but the factors that determine their susceptibility are poorly understood. Toxic increases in intracellular calcium are a key factor in several neurodegenerative processes, with calcium-binding proteins providing an important first line of defense through their ability [...] Read more.
Neuronal subpopulations display differential vulnerabilities to disease, but the factors that determine their susceptibility are poorly understood. Toxic increases in intracellular calcium are a key factor in several neurodegenerative processes, with calcium-binding proteins providing an important first line of defense through their ability to buffer incoming calcium, allowing the neuron to quickly achieve homeostasis. Since neurons expressing different calcium-binding proteins have been reported to be differentially susceptible to degeneration, it can be hypothesized that rather than just serving as markers of different neuronal subpopulations, they might actually be a key determinant of survival. In this review, we will summarize some of the evidence that expression of the EF-hand calcium-binding proteins, calbindin, calretinin and parvalbumin, may influence the susceptibility of distinct neuronal subpopulations to disease processes. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)
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