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Calcium-Binding Proteins and Cell Signaling

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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) | Viewed by 46816

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Prof. Dr. Masatoshi Maki

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Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
Interests: calcium-binding protein; calcium signaling; protein-protein interaction; post-transcriptional regulation; protein structure; membrane traffic
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Dr. Hideki Shibata

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Guest Editor

Department of Applied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan
Interests: calcium-binding protein; membrane traffic
Special Issues, Collections and Topics in MDPI journals

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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
Dr. Hideki Shibata
Guest Editors

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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

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Related Special Issues

Calcium-Binding Proteins and Cell Signaling 2.0 in International Journal of Molecular Sciences (18 articles)
Calcium-Binding Proteins and Cell Signaling 3.0 in International Journal of Molecular Sciences (28 articles)
Calcium-Binding Proteins and Cell Signaling, 4th Edition in International Journal of Molecular Sciences

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Research

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18 pages, 1850 KiB

Open AccessArticle

Methylene Blue Blocks and Reverses the Inhibitory Effect of Tau on PMCA Function

by Maria Berrocal, Montaña Caballero-Bermejo, Carlos Gutierrez-Merino and Ana M. Mata

Int. J. Mol. Sci. 2019, 20(14), 3521; https://doi.org/10.3390/ijms20143521 - 18 Jul 2019

Cited by 14 | Viewed by 5526

Abstract

Methylene blue (MB) is a synthetic phenothiazine dye that, in the last years, has generated much debate about whether it could be a useful therapeutic drug for tau-related pathologies, such as Alzheimer’s disease (AD). However, the molecular mechanism of action is far from clear. Recently we reported that MB activates the plasma membrane Ca²⁺-ATPase (PMCA) in membranes from human and pig tissues and from cells cultures, and that it could protect against inactivation of PMCA by amyloid β-peptide (Aβ). The purpose of the present study is to further examine whether the MB could also modulate the inhibitory effect of tau, another key molecular marker of AD, on PMCA activity. By using kinetic assays in membranes from several tissues and cell cultures, we found that this phenothiazine was able to block and even to completely reverse the inhibitory effect of tau on PMCA. The results of this work point out that MB could mediate the toxic effect of tau related to the deregulation of calcium homeostasis by blocking the impairment of PMCA activity by tau. We then could conclude that MB could interfere with the toxic effects of tau by restoring the function of PMCA pump as a fine tuner of calcium homeostasis. Full article

(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)

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22 pages, 5606 KiB

Open AccessArticle

Changes of Thermostability, Organic Solvent, and pH Stability in Geobacillus zalihae HT1 and Its Mutant by Calcium Ion

by Siti Nor Hasmah Ishak, Malihe Masomian, Nor Hafizah Ahmad Kamarudin, Mohd Shukuri Mohamad Ali, Thean Chor Leow and Raja Noor Zaliha Raja Abd. Rahman

Int. J. Mol. Sci. 2019, 20(10), 2561; https://doi.org/10.3390/ijms20102561 - 24 May 2019

Cited by 24 | Viewed by 5087

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 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 (T_m). 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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12 pages, 2080 KiB

Open AccessArticle

Inhibition of Calcium/Calmodulin-Dependent Protein Kinase Kinase β Is Detrimental in Hypoxia–Ischemia Neonatal Brain Injury

by Jia-Wei Min, Fan Bu, Li Qi, Yashasvee Munshi, Gab Seok Kim, Sean P. Marrelli, Louise D. McCullough and Jun Li

Int. J. Mol. Sci. 2019, 20(9), 2063; https://doi.org/10.3390/ijms20092063 - 26 Apr 2019

Cited by 6 | Viewed by 3803

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 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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15 pages, 2017 KiB

Open AccessArticle

Metabolic Inhibition Induces Transient Increase of L-type Ca²⁺ Current in Human and Rat Cardiac Myocytes

by Rimantas Treinys, Giedrius Kanaporis, Rodolphe Fischmeister and Jonas Jurevičius

Int. J. Mol. Sci. 2019, 20(6), 1501; https://doi.org/10.3390/ijms20061501 - 26 Mar 2019

Cited by 7 | Viewed by 4110

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 LTCC current (I_CaL) in human and rat cardiac myocytes: an initial increase of I_CaL 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 I_CaL 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 I_CaL in single cardiac myocytes. The initial increase of I_CaL was induced by a wide range of metabolic inhibitors (FCCP, 2,4-DNP, rotenone, antimycin A). In rat cardiomyocytes, the initial increase of I_CaL 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 I_CaL 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 I_CaL when Ca²⁺ was replaced by Ba²⁺, eliminating CDI of LTCCs. We conclude that the initial increase in I_CaL 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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17 pages, 4525 KiB

Open AccessArticle

Inhibition of Triple-Negative Breast Cancer Cell Aggressiveness by Cathepsin D Blockage: Role of Annexin A1

by Mariana Alves Pereira Zóia, Fernanda Van Petten Azevedo, Lara Vecchi, Sara Teixeira Soares Mota, Vinícius de Rezende Rodovalho, Antonielle Oliveira Cordeiro, Lucas Ian Veloso Correia, Anielle Christine Almeida Silva, Veridiana de Melo Rodrigues Ávila, Thaise Gonçalves de Araújo and Luiz Ricardo Goulart

Int. J. Mol. Sci. 2019, 20(6), 1337; https://doi.org/10.3390/ijms20061337 - 16 Mar 2019

Cited by 17 | Viewed by 4406

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 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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22 pages, 2740 KiB

Open AccessReview

Calcium Mechanisms in Limb-Girdle Muscular Dystrophy with CAPN3 Mutations

by Jaione Lasa-Elgarresta, Laura Mosqueira-Martín, Neia Naldaiz-Gastesi, Amets Sáenz, Adolfo López de Munain and Ainara Vallejo-Illarramendi

Int. J. Mol. Sci. 2019, 20(18), 4548; https://doi.org/10.3390/ijms20184548 - 13 Sep 2019

Cited by 27 | Viewed by 7235

Abstract

Limb-girdle muscular dystrophy recessive 1 (LGMDR1), previously known as LGMD2A, is a rare disease caused by mutations in the CAPN3 gene. It is characterized by progressive weakness of shoulder, pelvic, and proximal limb muscles that usually appears in children and young adults and results in loss of ambulation within 20 years after disease onset in most patients. The pathophysiological mechanisms involved in LGMDR1 remain mostly unknown, and to date, there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of Ca²⁺ homeostasis in the skeletal muscle is a significant underlying event in this muscular dystrophy. We also review and discuss specific clinical features of LGMDR1, CAPN3 functions, novel putative targets for therapeutic strategies, and current approaches aiming to treat LGMDR1. These novel approaches may be clinically relevant not only for LGMDR1 but also for other muscular dystrophies with secondary calpainopathy or with abnormal Ca²⁺ homeostasis, such as LGMD2B/LGMDR2 or sporadic inclusion body myositis. Full article

(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling)

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28 pages, 2069 KiB

Open AccessReview

Calcium-Binding Proteins in the Nervous System during Hibernation: Neuroprotective Strategies in Hypometabolic Conditions?

by Giacomo Gattoni and Graziella Bernocchi

Int. J. Mol. Sci. 2019, 20(9), 2364; https://doi.org/10.3390/ijms20092364 - 13 May 2019

Cited by 12 | Viewed by 5496

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 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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22 pages, 1577 KiB

Open AccessReview

Expression of Ca²⁺-Binding Buffer Proteins in the Human and Mouse Retinal Neurons

by Tamás Kovács-Öller, Gergely Szarka, Alma Ganczer, Ádám Tengölics, Boglárka Balogh and Béla Völgyi

Int. J. Mol. Sci. 2019, 20(9), 2229; https://doi.org/10.3390/ijms20092229 - 7 May 2019

Cited by 18 | Viewed by 4613

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, 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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14 pages, 813 KiB

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Calcium-Binding Proteins as Determinants of Central Nervous System Neuronal Vulnerability to Disease

by Richard Fairless, Sarah K. Williams and Ricarda Diem

Int. J. Mol. Sci. 2019, 20(9), 2146; https://doi.org/10.3390/ijms20092146 - 30 Apr 2019

Cited by 73 | Viewed by 5912

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 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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