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Calcium-Binding Proteins and Cell Signaling 3.0

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

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 27471

Special Issue Editors

Prof. Dr. Masatoshi Maki

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals
Dr. Hideki Shibata

E-Mail Website
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

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 cells are strictly regulated by Ca2+-sensing proteins, channels, and 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. The nuclear roles of Ca2+ in transcriptional and post-transcriptional regulation are also drawing 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 the 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; plants, lower eukaryotes, and some bacteria also use Ca2+ as a signaling molecule. This Special Issue, “Calcium-Binding Proteins and Cell Signaling”, welcomes contributions covering all areas of basic and application-oriented research associated with calcium regarding the aspects of biochemistry, cell biology, molecular biology, and biophysics.

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

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20 pages, 2808 KiB  
Article
Ca2+ Homeostasis by Plasma Membrane Ca2+ ATPase (PMCA) 1 Is Essential for the Development of DP Thymocytes
by David Beckmann, Kristina Langnaese, Anna Gottfried, Johannes Hradsky, Kerry Tedford, Nikhil Tiwari, Ulrich Thomas, Klaus-Dieter Fischer and Mark Korthals
Int. J. Mol. Sci. 2023, 24(2), 1442; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021442 - 11 Jan 2023
Viewed by 1689
Abstract
The strength of Ca2+ signaling is a hallmark of T cell activation, yet the role of Ca2+ homeostasis in developing T cells before expressing a mature T cell receptor is poorly understood. We aimed to unveil specific functions of the two [...] Read more.
The strength of Ca2+ signaling is a hallmark of T cell activation, yet the role of Ca2+ homeostasis in developing T cells before expressing a mature T cell receptor is poorly understood. We aimed to unveil specific functions of the two plasma membrane Ca2+ ATPases expressed in T cells, PMCA1 and PMCA4. On a transcriptional and protein level we found that PMCA4 was expressed at low levels in CD4−CD8− double negative (DN) thymocytes and was even downregulated in subsequent stages while PMCA1 was present throughout development and upregulated in CD4+CD8+ double positive (DP) thymocytes. Mice with a targeted deletion of Pmca1 in DN3 thymocytes had an almost complete block of DP thymocyte development with an accumulation of DN4 thymocytes but severely reduced numbers of CD8+ immature single positive (ISP) thymocytes. The DN4 thymocytes of these mice showed strongly elevated basal cytosolic Ca2+ levels and a pre-mature CD5 expression, but in contrast to the DP thymocytes they were only mildly prone to apoptosis. Surprisingly, mice with a germline deletion of Pmca4 did not show any signs of altered progression through the developmental thymocyte stages, nor altered Ca2+ homeostasis throughout this process. PMCA1 is, therefore, non-redundant in keeping cellular Ca2+ levels low in the early thymocyte development required for the DN to DP transition. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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22 pages, 5172 KiB  
Article
Neuronal Calcium Sensor-1 Protects Cortical Neurons from Hyperexcitation and Ca2+ Overload during Ischemia by Protecting the Population of GABAergic Neurons
by Elena G. Varlamova, Egor Y. Plotnikov and Egor A. Turovsky
Int. J. Mol. Sci. 2022, 23(24), 15675; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415675 - 10 Dec 2022
Cited by 4 | Viewed by 1523
Abstract
A defection of blood circulation in the brain leads to ischemia, damage, and the death of nerve cells. It is known that individual populations of GABAergic neurons are the least resistant to the damaging factors of ischemia and therefore they die first of [...] Read more.
A defection of blood circulation in the brain leads to ischemia, damage, and the death of nerve cells. It is known that individual populations of GABAergic neurons are the least resistant to the damaging factors of ischemia and therefore they die first of all, which leads to impaired inhibition in neuronal networks. To date, the neuroprotective properties of a number of calcium-binding proteins (calbindin, calretinin, and parvalbumin), which are markers of GABAergic neurons, are known. Neuronal calcium sensor-1 (NCS-1) is a signaling protein that is expressed in all types of neurons and is involved in the regulation of neurotransmission. The role of NCS-1 in the protection of neurons and especially their individual populations from ischemia and hyperexcitation has not been practically studied. In this work, using the methods of fluorescence microscopy, vitality tests, immunocytochemistry, and PCR analysis, the molecular mechanisms of the protective action of NCS-1 in ischemia/reoxygenation and hyperammonemia were established. Since NCS-1 is most expressed in GABAergic neurons, the knockdown of this protein with siRNA led to the most pronounced consequences in GABAergic neurons. The knockdown of NCS-1 (NCS-1-KD) suppressed the basic expression of protective proteins without significantly reducing cell viability. However, ischemia-like conditions (oxygen-glucose deprivation, OGD) and subsequent 24-h reoxygenation led to a more massive activation of apoptosis and necrosis in neurons with NCS-1-KD, compared to control cells. The mass death of NCS-1-KD cells during OGD and hyperammonemia has been associated with the induction of a more pronounced network hyperexcitation symptom, especially in the population of GABAergic neurons, leading to a global increase in cytosolic calcium ([Ca2+]i). The symptom of hyperexcitation of neurons with NCS-1-KD correlated with a decrease in the level of expression of the calcium-binding protein-parvalbumin. This was accompanied by an increase in the expression of excitatory ionotropic glutamate receptors, N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (NMDAR and AMPAR) against the background of suppression of the expression of glutamate decarboxylase (synthesis of γ-aminobutyric acid). Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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15 pages, 1986 KiB  
Article
Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells
by Nahoko Tomonobu, Rie Kinoshita, Hidenori Wake, Yusuke Inoue, I Made Winarsa Ruma, Ken Suzawa, Yuma Gohara, Ni Luh Gede Yoni Komalasari, Fan Jiang, Hitoshi Murata, Ken-ichi Yamamoto, I Wayan Sumardika, Youyi Chen, Junichiro Futami, Akira Yamauchi, Futoshi Kuribayashi, Eisaku Kondo, Shinichi Toyooka, Masahiro Nishibori and Masakiyo Sakaguchi
Int. J. Mol. Sci. 2022, 23(18), 10300; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810300 - 07 Sep 2022
Cited by 4 | Viewed by 2134
Abstract
The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, [...] Read more.
The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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12 pages, 1919 KiB  
Article
Expression of the Calcium-Binding Protein CALB1 Is Induced and Controls Intracellular Ca2+ Levels in Senescent Cells
by Clotilde Raynard, Nolwenn Tessier, Anda Huna, Marine Warnier, Jean-Michel Flaman, Fabien Van Coppenolle, Sylvie Ducreux, Nadine Martin and David Bernard
Int. J. Mol. Sci. 2022, 23(16), 9376; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169376 - 19 Aug 2022
Cited by 10 | Viewed by 2154
Abstract
In response to many stresses, such as oncogene activation or DNA damage, cells can enter cellular senescence, a state of proliferation arrest accompanied by a senescence-associated secretory phenotype (SASP). Cellular senescence plays a key role in many physiopathological contexts, including cancer, aging and [...] Read more.
In response to many stresses, such as oncogene activation or DNA damage, cells can enter cellular senescence, a state of proliferation arrest accompanied by a senescence-associated secretory phenotype (SASP). Cellular senescence plays a key role in many physiopathological contexts, including cancer, aging and aging-associated diseases, therefore, it is critical to understand how senescence is regulated. Calcium ions (Ca2+) recently emerged as pivotal regulators of cellular senescence. However, how Ca2+ levels are controlled during this process is barely known. Here, we report that intracellular Ca2+ contents increase in response to many senescence inducers in immortalized human mammary epithelial cells (HMECs) and that expression of calbindin 1 (CALB1), a Ca2+-binding protein, is upregulated in this context, through the Ca2+-dependent calcineurin/NFAT pathway. We further show that overexpression of CALB1 buffers the rise in intracellular Ca2+ levels observed in senescent cells. Finally, we suggest that increased expression of Ca2+-binding proteins calbindins is a frequent mark of senescent cells. This work thus supports that, together with Ca2+channels, Ca2+-binding proteins modulate Ca2+ levels and flux during cellular senescence. This opens potential avenues of research to better understand the role of Ca2+ and of Ca2+-binding proteins in regulating cellular senescence. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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19 pages, 16002 KiB  
Article
Snapin Specifically Up-Regulates Cav1.3 Ca2+ Channel Variant with a Long Carboxyl Terminus
by Sua Jeong, Jeong-Seop Rhee and Jung-Ha Lee
Int. J. Mol. Sci. 2021, 22(20), 11268; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011268 - 19 Oct 2021
Cited by 1 | Viewed by 1611
Abstract
Ca2+ entry through Cav1.3 Ca2+ channels plays essential roles in diverse physiological events. We employed yeast-two-hybrid (Y2H) assays to mine novel proteins interacting with Cav1.3 and found Snapin2, a synaptic protein, as a partner interacting with the [...] Read more.
Ca2+ entry through Cav1.3 Ca2+ channels plays essential roles in diverse physiological events. We employed yeast-two-hybrid (Y2H) assays to mine novel proteins interacting with Cav1.3 and found Snapin2, a synaptic protein, as a partner interacting with the long carboxyl terminus (CTL) of rat Cav1.3L variant. Co-expression of Snapin with Cav1.3L/Cavβ3/α2δ2 subunits increased the peak current density or amplitude by about 2-fold in HEK-293 cells and Xenopus oocytes, without affecting voltage-dependent gating properties and calcium-dependent inactivation. However, the Snapin up-regulation effect was not found for rat Cav1.3S containing a short CT (CTS) in which a Snapin interaction site in the CTL was deficient. Luminometry and electrophysiology studies uncovered that Snapin co-expression did not alter the membrane expression of HA tagged Cav1.3L but increased the slope of tail current amplitudes plotted against ON-gating currents, indicating that Snapin increases the opening probability of Cav1.3L. Taken together, our results strongly suggest that Snapin directly interacts with the CTL of Cav1.3L, leading to up-regulation of Cav1.3L channel activity via facilitating channel opening probability. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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15 pages, 3320 KiB  
Article
Atomistic Structure and Dynamics of the Ca2+-ATPase Bound to Phosphorylated Phospholamban
by Rodrigo Aguayo-Ortiz and L. Michel Espinoza-Fonseca
Int. J. Mol. Sci. 2020, 21(19), 7261; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197261 - 01 Oct 2020
Cited by 6 | Viewed by 1947
Abstract
Sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLB) are essential components of the cardiac Ca2+ transport machinery. PLB phosphorylation at residue Ser16 (pSer16) enhances SERCA activity in the heart via an unknown structural mechanism. Here, we report a fully atomistic model [...] Read more.
Sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLB) are essential components of the cardiac Ca2+ transport machinery. PLB phosphorylation at residue Ser16 (pSer16) enhances SERCA activity in the heart via an unknown structural mechanism. Here, we report a fully atomistic model of SERCA bound to phosphorylated PLB and study its structural dynamics on the microsecond time scale using all-atom molecular dynamics simulations in an explicit lipid bilayer and water environment. The unstructured N-terminal phosphorylation domain of PLB samples different orientations and covers a broad area of the cytosolic domain of SERCA but forms a stable complex mediated by pSer16 interactions with a binding site formed by SERCA residues Arg324/Lys328. PLB phosphorylation does not affect the interaction between the transmembrane regions of the two proteins; however, pSer16 stabilizes a disordered structure of the N-terminal phosphorylation domain that releases key inhibitory contacts between SERCA and PLB. We found that PLB phosphorylation is sufficient to guide the structural transitions of the cytosolic headpiece that are required to produce a competent structure of SERCA. We conclude that PLB phosphorylation serves as an allosteric molecular switch that releases inhibitory contacts and strings together the catalytic elements required for SERCA activation. This atomistic model represents a vivid atomic-resolution visualization of SERCA bound to phosphorylated PLB and provides previously inaccessible insights into the structural mechanism by which PLB phosphorylation releases SERCA inhibition in the heart. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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21 pages, 3570 KiB  
Article
The Penta-EF-Hand ALG-2 Protein Interacts with the Cytosolic Domain of the SOCE Regulator SARAF and Interferes with Ubiquitination
by Wei Zhang, Ayaka Muramatsu, Rina Matsuo, Naoki Teranishi, Yui Kahara, Terunao Takahara, Hideki Shibata and Masatoshi Maki
Int. J. Mol. Sci. 2020, 21(17), 6315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176315 - 31 Aug 2020
Cited by 7 | Viewed by 2721
Abstract
ALG-2 is a penta-EF-hand Ca2+-binding protein and interacts with a variety of proteins in mammalian cells. In order to find new ALG-2-binding partners, we searched a human protein database and retrieved sequences containing the previously identified ALG-2-binding motif type 2 (ABM-2). [...] Read more.
ALG-2 is a penta-EF-hand Ca2+-binding protein and interacts with a variety of proteins in mammalian cells. In order to find new ALG-2-binding partners, we searched a human protein database and retrieved sequences containing the previously identified ALG-2-binding motif type 2 (ABM-2). After selecting 12 high-scored sequences, we expressed partial or full-length GFP-fused proteins in HEK293 cells and performed a semi-quantitative in vitro binding assay. SARAF, a negative regulator of store-operated Ca2+ entry (SOCE), showed the strongest binding activity. Biochemical analysis of Strep-tagged and GFP-fused SARAF proteins revealed ubiquitination that proceeded during pulldown assays under certain buffer conditions. Overexpression of ALG-2 interfered with ubiquitination of wild-type SARAF but not ubiquitination of the F228S mutant that had impaired ALG-2-binding activity. The SARAF cytosolic domain (CytD) contains two PPXY motifs targeted by the WW domains of NEDD4 family E3 ubiquitin ligases. The PPXY motif proximal to the ABM-2 sequence was found to be more important for both in-cell ubiquitination and post-cell lysis ubiquitination. A ubiquitination-defective mutant of SARAF with Lys-to-Arg substitutions in the CytD showed a slower degradation rate by half-life analysis. ALG-2 promoted Ca2+-dependent CytD-to-CytD interactions of SARAF. The ALG-2 dimer may modulate the stability of SARAF by sterically blocking ubiquitination and by bridging SARAF molecules at the CytDs. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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21 pages, 4979 KiB  
Article
Knockout of stim2a Increases Calcium Oscillations in Neurons and Induces Hyperactive-Like Phenotype in Zebrafish Larvae
by Rishikesh Kumar Gupta, Iga Wasilewska, Oksana Palchevska and Jacek Kuźnicki
Int. J. Mol. Sci. 2020, 21(17), 6198; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176198 - 27 Aug 2020
Cited by 8 | Viewed by 2765
Abstract
Stromal interaction molecule (STIM) proteins play a crucial role in store-operated calcium entry (SOCE) as endoplasmic reticulum Ca2+ sensors. In neurons, STIM2 was shown to have distinct functions from STIM1. However, its role in brain activity and behavior was not fully elucidated. [...] Read more.
Stromal interaction molecule (STIM) proteins play a crucial role in store-operated calcium entry (SOCE) as endoplasmic reticulum Ca2+ sensors. In neurons, STIM2 was shown to have distinct functions from STIM1. However, its role in brain activity and behavior was not fully elucidated. The present study analyzed behavior in zebrafish (Danio rerio) that lacked stim2a. The mutant animals had no morphological abnormalities and were fertile. RNA-sequencing revealed alterations of the expression of transcription factor genes and several members of the calcium toolkit. Neuronal Ca2+ activity was measured in vivo in neurons that expressed the GCaMP5G sensor. Optic tectum neurons in stim2a−/− fish had more frequent Ca2+ signal oscillations compared with neurons in wildtype (WT) fish. We detected an increase in activity during the visual–motor response test, an increase in thigmotaxis in the open field test, and the disruption of phototaxis in the dark/light preference test in stim2a−/− mutants compared with WT. Both groups of animals reacted to glutamate and pentylenetetrazol with an increase in activity during the visual–motor response test, with no major differences between groups. Altogether, our results suggest that the hyperactive-like phenotype of stim2a−/− mutant zebrafish is caused by the dysregulation of Ca2+ homeostasis and signaling. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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28 pages, 5574 KiB  
Article
Distinct and Overlapping Expression Patterns of the Homer Family of Scaffolding Proteins and Their Encoding Genes in Developing Murine Cephalic Tissues
by Claes-Göran Reibring, Kristina Hallberg, Anders Linde and Amel Gritli-Linde
Int. J. Mol. Sci. 2020, 21(4), 1264; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041264 - 13 Feb 2020
Cited by 7 | Viewed by 2909
Abstract
In mammals Homer1, Homer2 and Homer3 constitute a family of scaffolding proteins with key roles in Ca2+ signaling and Ca2+ transport. In rodents, Homer proteins and mRNAs have been shown to be expressed in various postnatal tissues and to be enriched [...] Read more.
In mammals Homer1, Homer2 and Homer3 constitute a family of scaffolding proteins with key roles in Ca2+ signaling and Ca2+ transport. In rodents, Homer proteins and mRNAs have been shown to be expressed in various postnatal tissues and to be enriched in brain. However, whether the Homers are expressed in developing tissues is hitherto largely unknown. In this work, we used immunohistochemistry and in situ hybridization to analyze the expression patterns of Homer1, Homer2 and Homer3 in developing cephalic structures. Our study revealed that the three Homer proteins and their encoding genes are expressed in a wide range of developing tissues and organs, including the brain, tooth, eye, cochlea, salivary glands, olfactory and respiratory mucosae, bone and taste buds. We show that although overall the three Homers exhibit overlapping distribution patterns, the proteins localize at distinct subcellular domains in several cell types, that in both undifferentiated and differentiated cells Homer proteins are concentrated in puncta and that the vascular endothelium is enriched with Homer3 mRNA and protein. Our findings suggest that Homer proteins may have differential and overlapping functions and are expected to be of value for future research aiming at deciphering the roles of Homer proteins during embryonic development. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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19 pages, 5369 KiB  
Article
Constitutive Activation of Guanylate Cyclase by the G86R GCAP1 Variant Is Due to “Locking” Cation-π Interactions that Impair the Activator-to-Inhibitor Structural Transition
by Seher Abbas, Valerio Marino, Laura Bielefeld, Karl-Wilhelm Koch and Daniele Dell’Orco
Int. J. Mol. Sci. 2020, 21(3), 752; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030752 - 23 Jan 2020
Cited by 6 | Viewed by 2621
Abstract
Guanylate Cyclase activating protein 1 (GCAP1) mediates the Ca2+-dependent regulation of the retinal Guanylate Cyclase (GC) in photoreceptors, acting as a target inhibitor at high [Ca2+] and as an activator at low [Ca2+]. Recently, a novel missense [...] Read more.
Guanylate Cyclase activating protein 1 (GCAP1) mediates the Ca2+-dependent regulation of the retinal Guanylate Cyclase (GC) in photoreceptors, acting as a target inhibitor at high [Ca2+] and as an activator at low [Ca2+]. Recently, a novel missense mutation (G86R) was found in GUCA1A, the gene encoding for GCAP1, in patients diagnosed with cone-rod dystrophy. The G86R substitution was found to affect the flexibility of the hinge region connecting the N- and C-domains of GCAP1, resulting in decreased Ca2+-sensitivity and abnormally enhanced affinity for GC. Based on a structural model of GCAP1, here, we tested the hypothesis of a cation-π interaction between the positively charged R86 and the aromatic W94 as the main mechanism underlying the impaired activator-to-inhibitor conformational change. W94 was mutated to F or L, thus, resulting in the double mutants G86R+W94L/F. The double mutants showed minor structural and stability changes with respect to the single G86R mutant, as well as lower affinity for both Mg2+ and Ca2+, moreover, substitutions of W94 abolished “phase II” in Ca2+-titrations followed by intrinsic fluorescence. Interestingly, the presence of an aromatic residue in position 94 significantly increased the aggregation propensity of Ca2+-loaded GCAP1 variants. Finally, atomistic simulations of all GCAP1 variants in the presence of Ca2+ supported the presence of two cation-π interactions involving R86, which was found to act as a bridge between W94 and W21, thus, locking the hinge region in an activator-like conformation and resulting in the constitutive activation of the target under physiological conditions. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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18 pages, 1850 KiB  
Article
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143521 - 18 Jul 2019
Cited by 13 | Viewed by 4972
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 [...] Read more.
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  
Article
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102561 - 24 May 2019
Cited by 19 | Viewed by 4413
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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12 pages, 2080 KiB  
Article
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092063 - 26 Apr 2019
Cited by 6 | Viewed by 3471
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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15 pages, 2017 KiB  
Article
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061501 - 26 Mar 2019
Cited by 4 | Viewed by 3743
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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17 pages, 4525 KiB  
Article
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061337 - 16 Mar 2019
Cited by 14 | Viewed by 3990
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

Jump to: Research

19 pages, 2272 KiB  
Review
New Insights into the Regulation of mTOR Signaling via Ca2+-Binding Proteins
by Yuna Amemiya, Masatoshi Maki, Hideki Shibata and Terunao Takahara
Int. J. Mol. Sci. 2023, 24(4), 3923; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043923 - 15 Feb 2023
Cited by 5 | Viewed by 5049
Abstract
Environmental factors are important regulators of cell growth and proliferation. Mechanistic target of rapamycin (mTOR) is a central kinase that maintains cellular homeostasis in response to a variety of extracellular and intracellular inputs. Dysregulation of mTOR signaling is associated with many diseases, including [...] Read more.
Environmental factors are important regulators of cell growth and proliferation. Mechanistic target of rapamycin (mTOR) is a central kinase that maintains cellular homeostasis in response to a variety of extracellular and intracellular inputs. Dysregulation of mTOR signaling is associated with many diseases, including diabetes and cancer. Calcium ion (Ca2+) is important as a second messenger in various biological processes, and its intracellular concentration is tightly regulated. Although the involvement of Ca2+ mobilization in mTOR signaling has been reported, the detailed molecular mechanisms by which mTOR signaling is regulated are not fully understood. The link between Ca2+ homeostasis and mTOR activation in pathological hypertrophy has heightened the importance in understanding Ca2+-regulated mTOR signaling as a key mechanism of mTOR regulation. In this review, we introduce recent findings on the molecular mechanisms of regulation of mTOR signaling by Ca2+-binding proteins, particularly calmodulin (CaM). Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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17 pages, 1560 KiB  
Review
Calcium-Signalling in Human Glaucoma Lamina Cribrosa Myofibroblasts
by Mustapha Irnaten and Colm J. O’Brien
Int. J. Mol. Sci. 2023, 24(2), 1287; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021287 - 09 Jan 2023
Cited by 3 | Viewed by 1589
Abstract
Glaucoma is one of the most common causes of treatable visual impairment in the developed world, affecting approximately 64 million people worldwide, some of whom will be bilaterally blind from irreversible optic nerve damage. The optic nerve head is a key site of [...] Read more.
Glaucoma is one of the most common causes of treatable visual impairment in the developed world, affecting approximately 64 million people worldwide, some of whom will be bilaterally blind from irreversible optic nerve damage. The optic nerve head is a key site of damage in glaucoma where there is fibrosis of the connective tissue in the lamina cribrosa (LC) extracellular matrix. As a ubiquitous second messenger, calcium (Ca2+) can interact with various cellular proteins to regulate multiple physiological processes and contribute to a wide range of diseases, including cancer, fibrosis, and glaucoma. Our research has shown evidence of oxidative stress, mitochondrial dysfunction, an elevated expression of Ca2+ entry channels, Ca2+-dependent pumps and exchangers, and an abnormal rise in cytosolic Ca2+ in human glaucomatous LC fibroblast cells. We have evidence that this increase is dependent on Ca2+ entry channels located in the plasma membrane, and its release is from internal stores in the endoplasmic reticulum (ER), as well as from the mitochondria. Here, we summarize some of the molecular Ca2+-dependent mechanisms related to this abnormal Ca2+-signalling in human glaucoma LC cells, with a view toward identifying potential therapeutic targets for ongoing optic neuropathy. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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19 pages, 2919 KiB  
Review
Molecular Mechanisms Underlying Ca2+/Calmodulin-Dependent Protein Kinase Kinase Signal Transduction
by Hiroshi Tokumitsu and Hiroyuki Sakagami
Int. J. Mol. Sci. 2022, 23(19), 11025; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911025 - 20 Sep 2022
Cited by 22 | Viewed by 3400
Abstract
Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) is the activating kinase for multiple downstream kinases, including CaM-kinase I (CaMKI), CaM-kinase IV (CaMKIV), protein kinase B (PKB/Akt), and 5′AMP-kinase (AMPK), through the phosphorylation of their activation-loop Thr residues in response to increasing the intracellular [...] Read more.
Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) is the activating kinase for multiple downstream kinases, including CaM-kinase I (CaMKI), CaM-kinase IV (CaMKIV), protein kinase B (PKB/Akt), and 5′AMP-kinase (AMPK), through the phosphorylation of their activation-loop Thr residues in response to increasing the intracellular Ca2+ concentration, as CaMKK itself is a Ca2+/CaM-dependent enzyme. The CaMKK-mediated kinase cascade plays important roles in a number of Ca2+-dependent pathways, such as neuronal morphogenesis and plasticity, transcriptional activation, autophagy, and metabolic regulation, as well as in pathophysiological pathways, including cancer progression, metabolic syndrome, and mental disorders. This review focuses on the molecular mechanism underlying CaMKK-mediated signal transduction in normal and pathophysiological conditions. We summarize the current knowledge of the structural, functional, and physiological properties of the regulatory kinase, CaMKK, and the development and application of its pharmacological inhibitors. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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16 pages, 2245 KiB  
Review
Structure, Function and Regulation of the Plasma Membrane Calcium Pump in Health and Disease
by Joachim Krebs
Int. J. Mol. Sci. 2022, 23(3), 1027; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031027 - 18 Jan 2022
Cited by 13 | Viewed by 4320
Abstract
In this review, I summarize the present knowledge of the structural and functional properties of the mammalian plasma membrane calcium pump (PMCA). It is outlined how the cellular expression of the different spliced isoforms of the four genes are regulated under normal and [...] Read more.
In this review, I summarize the present knowledge of the structural and functional properties of the mammalian plasma membrane calcium pump (PMCA). It is outlined how the cellular expression of the different spliced isoforms of the four genes are regulated under normal and pathological conditions. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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18 pages, 2618 KiB  
Review
Structural Basis for the Functional Diversity of Centrins: A Focus on Calcium Sensing Properties and Target Recognition
by Marco Pedretti, Luca Bombardi, Carolina Conter, Filippo Favretto, Paola Dominici and Alessandra Astegno
Int. J. Mol. Sci. 2021, 22(22), 12173; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212173 - 10 Nov 2021
Cited by 6 | Viewed by 2463
Abstract
Centrins are a family of small, EF hand-containing proteins that are found in all eukaryotes and are often complexed with centrosome-related structures. Since their discovery, centrins have attracted increasing interest due to their multiple, diverse cellular functions. Centrins are similar to calmodulin (CaM) [...] Read more.
Centrins are a family of small, EF hand-containing proteins that are found in all eukaryotes and are often complexed with centrosome-related structures. Since their discovery, centrins have attracted increasing interest due to their multiple, diverse cellular functions. Centrins are similar to calmodulin (CaM) in size, structure and domain organization, although in contrast to CaM, the majority of centrins possess at least one calcium (Ca2+) binding site that is non-functional, thus displaying large variance in Ca2+ sensing abilities that could support their functional versatility. In this review, we summarize current knowledge on centrins from both biophysical and structural perspectives with an emphasis on centrin-target interactions. In-depth analysis of the Ca2+ sensing properties of centrins and structures of centrins complexed with target proteins can provide useful insight into the mechanisms of the different functions of centrins and how these proteins contribute to the complexity of the Ca2+ signaling cascade. Moreover, it can help to better understand the functional redundancy of centrin isoforms and centrin-binding proteins. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 3.0)
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20 pages, 1457 KiB  
Review
ASGR1 and Its Enigmatic Relative, CLEC10A
by J. Kenneth Hoober
Int. J. Mol. Sci. 2020, 21(14), 4818; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144818 - 08 Jul 2020
Cited by 27 | Viewed by 5852
Abstract
The large family of C-type lectin (CLEC) receptors comprises carbohydrate-binding proteins that require Ca2+ to bind a ligand. The prototypic receptor is the asialoglycoprotein receptor-1 (ASGR1, CLEC4H1) that is expressed primarily by hepatocytes. The early work on ASGR1, which is highly specific [...] Read more.
The large family of C-type lectin (CLEC) receptors comprises carbohydrate-binding proteins that require Ca2+ to bind a ligand. The prototypic receptor is the asialoglycoprotein receptor-1 (ASGR1, CLEC4H1) that is expressed primarily by hepatocytes. The early work on ASGR1, which is highly specific for N-acetylgalactosamine (GalNAc), established the foundation for understanding the overall function of CLEC receptors. Cells of the immune system generally express more than one CLEC receptor that serve diverse functions such as pathogen-recognition, initiation of cellular signaling, cellular adhesion, glycoprotein turnover, inflammation and immune responses. The receptor CLEC10A (C-type lectin domain family 10 member A, CD301; also called the macrophage galactose-type lectin, MGL) contains a carbohydrate-recognition domain (CRD) that is homologous to the CRD of ASGR1, and thus, is also specific for GalNAc. CLEC10A is most highly expressed on immature DCs, monocyte-derived DCs, and alternatively activated macrophages (subtype M2a) as well as oocytes and progenitor cells at several stages of embryonic development. This receptor is involved in initiation of TH1, TH2, and TH17 immune responses and induction of tolerance in naïve T cells. Ligand-mediated endocytosis of CLEC receptors initiates a Ca2+ signal that interestingly has different outcomes depending on ligand properties, concentration, and frequency of administration. This review summarizes studies that have been carried out on these receptors. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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32 pages, 5030 KiB  
Review
Linking Biochemical and Structural States of SERCA: Achievements, Challenges, and New Opportunities
by Rodrigo Aguayo-Ortiz and L. Michel Espinoza-Fonseca
Int. J. Mol. Sci. 2020, 21(11), 4146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114146 - 10 Jun 2020
Cited by 35 | Viewed by 6126
Abstract
Sarcoendoplasmic reticulum calcium ATPase (SERCA), a member of the P-type ATPase family of ion and lipid pumps, is responsible for the active transport of Ca2+ from the cytoplasm into the sarcoplasmic reticulum lumen of muscle cells, into the endoplasmic reticulum (ER) of [...] Read more.
Sarcoendoplasmic reticulum calcium ATPase (SERCA), a member of the P-type ATPase family of ion and lipid pumps, is responsible for the active transport of Ca2+ from the cytoplasm into the sarcoplasmic reticulum lumen of muscle cells, into the endoplasmic reticulum (ER) of non-muscle cells. X-ray crystallography has proven to be an invaluable tool in understanding the structural changes of SERCA, and more than 70 SERCA crystal structures representing major biochemical states (defined by bound ligand) have been deposited in the Protein Data Bank. Consequently, SERCA is one of the best characterized components of the calcium transport machinery in the cell. Emerging approaches in the field, including spectroscopy and molecular simulation, now help integrate and interpret this rich structural information to understand the conformational transitions of SERCA that occur during activation, inhibition, and regulation. In this review, we provide an overview of the crystal structures of SERCA, focusing on identifying metrics that facilitate structure-based categorization of major steps along the catalytic cycle. We examine the integration of crystallographic data with different biophysical approaches and computational methods to link biochemical and structural states of SERCA that are populated in the cell. Finally, we discuss the challenges and new opportunities in the field, including structural elucidation of functionally important and novel regulatory complexes of SERCA, understanding the structural basis of functional divergence among homologous SERCA regulators, and bridging the gap between basic and translational research directed toward therapeutic modulation of SERCA. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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19 pages, 1610 KiB  
Review
Intracellular Ca2+ Signalling in the Pathogenesis of Acute Pancreatitis: Recent Advances and Translational Perspectives
by Petra Pallagi, Tamara Madácsy, Árpád Varga and József Maléth
Int. J. Mol. Sci. 2020, 21(11), 4005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114005 - 03 Jun 2020
Cited by 39 | Viewed by 7523
Abstract
Intracellular Ca2+ signalling is a major signal transductional pathway in non-excitable cells, responsible for the regulation of a variety of physiological functions. In the secretory epithelial cells of the exocrine pancreas, such as acinar and ductal cells, intracellular Ca2+ elevation regulates [...] Read more.
Intracellular Ca2+ signalling is a major signal transductional pathway in non-excitable cells, responsible for the regulation of a variety of physiological functions. In the secretory epithelial cells of the exocrine pancreas, such as acinar and ductal cells, intracellular Ca2+ elevation regulates digestive enzyme secretion in acini or fluid and ion secretion in ductal cells. Although Ca2+ is a uniquely versatile orchestrator of epithelial physiology, unregulated global elevation of the intracellular Ca2+ concentration is an early trigger for the development of acute pancreatitis (AP). Regardless of the aetiology, different forms of AP all exhibit sustained intracellular Ca2+ elevation as a common hallmark. The release of endoplasmic reticulum (ER) Ca2+ stores by toxins (such as bile acids or fatty acid ethyl esters (FAEEs)) or increased intrapancreatic pressure activates the influx of extracellular Ca2+ via the Orai1 Ca2+ channel, a process known as store-operated Ca2+ entry (SOCE). Intracellular Ca2+ overload can lead to premature activation of trypsinogen in pancreatic acinar cells and impaired fluid and HCO3- secretion in ductal cells. Increased and unbalanced reactive oxygen species (ROS) production caused by sustained Ca2+ elevation further contributes to cell dysfunction, leading to mitochondrial damage and cell death. Translational studies of AP identified several potential target molecules that can be modified to prevent intracellular Ca2+ overload. One of the most promising drugs, a selective inhibitor of the Orai1 channel that has been shown to inhibit extracellular Ca2+ influx and protect cells from injury, is currently being tested in clinical trials. In this review, we will summarise the recent advances in the field, with a special focus on the translational aspects of the basic findings. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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13 pages, 981 KiB  
Review
Valosin-Containing Protein, a Calcium-Associated ATPase Protein, in Endoplasmic Reticulum and Mitochondrial Function and Its Implications for Diseases
by Xiaonan Sun and Hongyu Qiu
Int. J. Mol. Sci. 2020, 21(11), 3842; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113842 - 28 May 2020
Cited by 27 | Viewed by 4045
Abstract
Endoplasmic reticulum (ER) and mitochondrion are the key organelles in mammal cells and play crucial roles in a variety of biological functions in both physiological and pathological conditions. Valosin-containing protein (VCP), a newly identified calcium-associated ATPase protein, has been found to be involved [...] Read more.
Endoplasmic reticulum (ER) and mitochondrion are the key organelles in mammal cells and play crucial roles in a variety of biological functions in both physiological and pathological conditions. Valosin-containing protein (VCP), a newly identified calcium-associated ATPase protein, has been found to be involved in both ER and mitochondrial function. Impairment of VCP, caused by structural mutations or alterations of expressions, contributes to the development of various diseases, through an integrating effect on ER, mitochondria and the ubiquitin–proteasome system, by interfering with protein degradation, subcellular translocation and calcium homeostasis. Thus, understanding the role and the molecular mechanisms of VCP in these organelles brings new insights to the pathogenesis of the associated diseases, and leads to the discovery of new therapeutic strategies. In this review, we summarized the progress of studies on VCP, in terms of its regulation of ER and mitochondrial function and its implications for the associated diseases, focusing on the cancers, heart disease, and neurodegenerative disorders. Full article
(This article belongs to the Special Issue Calcium-Binding Proteins and Cell Signaling 2.0)
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22 pages, 2740 KiB  
Review
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184548 - 13 Sep 2019
Cited by 24 | Viewed by 6308
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 [...] Read more.
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  
Review
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092364 - 13 May 2019
Cited by 11 | Viewed by 4892
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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22 pages, 1577 KiB  
Review
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092229 - 07 May 2019
Cited by 17 | Viewed by 4176
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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14 pages, 813 KiB  
Review
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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092146 - 30 Apr 2019
Cited by 67 | Viewed by 5322
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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