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Calcium Signaling in Mammalian Cells: From Physiology to Pathology

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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 (20 January 2025) | Viewed by 20859

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Special Issue Editor

Dr. Sergei G. Gaidin

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Department of Intracellular Signaling, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, 142290 Pushchino, Russia
Interests: Ca²⁺ signaling; neuron-glia interaction; neurotransmission; gliotransmission; apoptosis and cell death; neuroprotection; G-protein coupled receptors

Special Issue Information

Dear Colleagues,

Calcium ion is a universal second messenger involved in numerous signaling cascades. The changes in intracellular Ca²⁺ concentration ([Ca²⁺]_i) regulate a wide repertoire of functions, such as exocytosis, gene expression, metabolism, proliferation, and cell death. In the case of excitable tissues, calcium signals with different spatiotemporal characteristics modulate and integrate the activity of myriads of cells. Intracellular Ca²⁺ homeostasis is maintained by Ca²⁺ ATPases, exchangers, ion channels, and buffer systems, including calcium-binding proteins, internal stores, and mitochondria. This machinery provides Ca²⁺ inflow and outflow, while G-protein coupled receptors are considered the key modulators of Ca²⁺ dynamics. Taking into account the pivotal role of Ca²⁺ in cellular physiology, it is not surprising that a disruption in Ca²⁺ handling may be the reason behind or consequence of different pathologies. In this regard, pharmacological correction of Ca²⁺ homeostasis may serve as a therapeutic approach for the treatment of several diseases. This Special Issue on “Calcium Signaling in Mammalian Cells: from Physiology to Pathology” welcomes research dealing with any aspects of intracellular Ca²⁺ signaling in mammalian cells in health and diseases.

Suitable topics include, but are not limited to:

Calcium signaling in excitable cells
General issues of Ca²⁺ signaling
Role of Ca²⁺ transporting systems, Ca²⁺ channels, Ca²⁺ buffers/sensors in cellular physiology
Ca²⁺ as a key factor of apoptosis
GPCR-mediated Ca²⁺ signaling

Dr. Sergei G. Gaidin
Guest Editor

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Keywords

Ca²⁺ signaling
excitable cells
Ca²⁺ transporting systems
calcium-binding proteins
calcium dysregulation
signal transduction
G-protein coupled receptors
apoptosis

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Published Papers (6 papers)

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Research

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14 pages, 3231 KiB

Open AccessArticle

UBA6 Inhibition Accelerates Lysosomal TRPML1 Depletion and Exosomal Secretion in Lung Cancer Cells

by Dongun Lee, Peter Chang-Whan Lee and Jeong Hee Hong

Int. J. Mol. Sci. 2024, 25(5), 2843; https://doi.org/10.3390/ijms25052843 - 29 Feb 2024

Cited by 1 | Viewed by 1967

Abstract

Ubiquitin-like modifier-activating enzyme 6 (UBA6) is a member of the E1 enzyme family, which initiates the ubiquitin–proteasome system (UPS). The UPS plays critical roles not only in protein degradation but also in various cellular functions, including neuronal signaling, myocardial remodeling, immune cell differentiation, and cancer development. However, the specific role of UBA6 in cellular functions is not fully elucidated in comparison with the roles of the UPS. It has been known that the E1 enzyme is associated with the motility of cancer cells. In this study, we verified the physiological roles of UBA6 in lung cancer cells through gene-silencing siRNA targeting UBA6 (siUBA6). The siUBA6 treatment attenuated the migration of H1975 cells, along with a decrease in lysosomal Ca²⁺ release. While autophagosomal proteins remained unchanged, lysosomal proteins, including TRPML1 and TPC2, were decreased in siUBA6-transfected cells. Moreover, siUBA6 induced the production of multivesicular bodies (MVBs), accompanied by an increase in MVB markers in siUBA6-transfected H1975 cells. Additionally, the expression of the exosomal marker CD63 and extracellular vesicles was increased by siUBA6 treatment. Our findings suggest that knock-down of UBA6 induces lysosomal TRPML1 depletion and inhibits endosomal trafficking to lysosome, and subsequently, leads to the accumulation of MVBs and enhanced exosomal secretion in lung cancer cells. Full article

(This article belongs to the Special Issue Calcium Signaling in Mammalian Cells: From Physiology to Pathology)

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16 pages, 2916 KiB

Open AccessArticle

Improved Workflow for Analysis of Vascular Myocyte Time-Series and Line-Scan Ca²⁺ Imaging Datasets

by Madison Boskind, Nikitha Nelapudi, Grace Williamson, Bobby Mendez, Rucha Juarez, Lubo Zhang, Arlin B. Blood, Christopher G. Wilson, Jose Luis Puglisi and Sean M. Wilson

Int. J. Mol. Sci. 2023, 24(11), 9729; https://doi.org/10.3390/ijms24119729 - 4 Jun 2023

Cited by 1 | Viewed by 1873

Abstract

Intracellular Ca²⁺ signals are key for the regulation of cellular processes ranging from myocyte contraction, hormonal secretion, neural transmission, cellular metabolism, transcriptional regulation, and cell proliferation. Measurement of cellular Ca²⁺ is routinely performed using fluorescence microscopy with biological indicators. Analysis of deterministic signals is reasonably straightforward as relevant data can be discriminated based on the timing of cellular responses. However, analysis of stochastic, slower oscillatory events, as well as rapid subcellular Ca²⁺ responses, takes considerable time and effort which often includes visual analysis by trained investigators, especially when studying signals arising from cells embedded in complex tissues. The purpose of the current study was to determine if full-frame time-series and line-scan image analysis workflow of Fluo-4 generated Ca²⁺ fluorescence data from vascular myocytes could be automated without introducing errors. This evaluation was addressed by re-analyzing a published “gold standard” full-frame time-series dataset through visual analysis of Ca²⁺ signals from recordings made in pulmonary arterial myocytes of en face arterial preparations. We applied a combination of data driven and statistical approaches with comparisons to our published data to assess the fidelity of the various approaches. Regions of interest with Ca²⁺ oscillations were detected automatically post hoc using the LCPro plug-in for ImageJ. Oscillatory signals were separated based on event durations between 4 and 40 s. These data were filtered based on cutoffs obtained from multiple methods and compared to the published manually curated “gold standard” dataset. Subcellular focal and rapid Ca²⁺ “spark” events from line-scan recordings were examined using SparkLab 5.8, which is a custom automated detection and analysis program. After filtering, the number of true positives, false positives, and false negatives were calculated through comparisons to visually derived “gold standard” datasets. Positive predictive value, sensitivity, and false discovery rates were calculated. There were very few significant differences between the automated and manually curated results with respect to quality of the oscillatory and Ca²⁺ spark events, and there were no systematic biases in the data curation or filtering techniques. The lack of statistical difference in event quality between manual data curation and statistically derived critical cutoff techniques leads us to believe that automated analysis techniques can be reliably used to analyze spatial and temporal aspects to Ca²⁺ imaging data, which will improve experiment workflow. Full article

(This article belongs to the Special Issue Calcium Signaling in Mammalian Cells: From Physiology to Pathology)

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23 pages, 4486 KiB

Open AccessArticle

Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice

by Marat A. Mukhamedyarov, Aydar N. Khabibrakhmanov, Venera F. Khuzakhmetova, Arthur R. Giniatullin, Guzalia F. Zakirjanova, Nikita V. Zhilyakov, Kamilla A. Mukhutdinova, Dmitry V. Samigullin, Pavel N. Grigoryev, Andrey V. Zakharov, Andrey L. Zefirov and Alexey M. Petrov

Int. J. Mol. Sci. 2023, 24(10), 9022; https://doi.org/10.3390/ijms24109022 - 19 May 2023

Cited by 10 | Viewed by 3054

Abstract

Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations of RNA-binding protein FUS are one of the common genetic reasons of ALS accompanied by a ‘dying back’ type of degeneration. Using fluorescent approaches and microelectrode recordings, the early structural and functional alterations in diaphragm neuromuscular junctions (NMJs) were studied in mutant FUS mice at the pre-onset stage. Lipid peroxidation and decreased staining with a lipid raft marker were found in the mutant mice. Despite the preservation of the end-plate structure, immunolabeling revealed an increase in levels of presynaptic proteins, SNAP-25 and synapsin 1. The latter can restrain Ca²⁺-dependent synaptic vesicle mobilization. Indeed, neurotransmitter release upon intense nerve stimulation and its recovery after tetanus and compensatory synaptic vesicle endocytosis were markedly depressed in FUS mice. There was a trend to attenuation of axonal [Ca²⁺]_in increase upon nerve stimulation at 20 Hz. However, no changes in neurotransmitter release and the intraterminal Ca²⁺ transient in response to low frequency stimulation or in quantal content and the synchrony of neurotransmitter release at low levels of external Ca²⁺ were detected. At a later stage, shrinking and fragmentation of end plates together with a decrease in presynaptic protein expression and disturbance of the neurotransmitter release timing occurred. Overall, suppression of synaptic vesicle exo–endocytosis upon intense activity probably due to alterations in membrane properties, synapsin 1 levels and Ca²⁺ kinetics could be an early sign of nascent NMJ pathology, which leads to neuromuscular contact disorganization. Full article

(This article belongs to the Special Issue Calcium Signaling in Mammalian Cells: From Physiology to Pathology)

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25 pages, 4955 KiB

Open AccessArticle

Ca²⁺-Dependent Effects of the Selenium-Sorafenib Nanocomplex on Glioblastoma Cells and Astrocytes of the Cerebral Cortex: Anticancer Agent and Cytoprotector

by Elena G. Varlamova, Venera V. Khabatova, Sergey V. Gudkov and Egor A. Turovsky

Int. J. Mol. Sci. 2023, 24(3), 2411; https://doi.org/10.3390/ijms24032411 - 26 Jan 2023

Cited by 12 | Viewed by 2553

Abstract

Despite the fact that sorafenib is recommended for the treatment of oncological diseases of the liver, kidneys, and thyroid gland, and recently it has been used for combination therapy of brain cancer of various genesis, there are still significant problems for its widespread and effective use. Among these problems, the presence of the blood–brain barrier of the brain and the need to use high doses of sorafenib, the existence of mechanisms for the redistribution of sorafenib and its release in the brain tissue, as well as the high resistance of gliomas and glioblastomas to therapy should be considered the main ones. Therefore, there is a need to create new methods for delivering sorafenib to brain tumors, enhancing the therapeutic potential of sorafenib and reducing the cytotoxic effects of active compounds on the healthy environment of tumors, and ideally, increasing the survival of healthy cells during therapy. Using vitality tests, fluorescence microscopy, and molecular biology methods, we showed that the selenium-sorafenib (SeSo) nanocomplex, at relatively low concentrations, is able to bypass the mechanisms of glioblastoma cell chemoresistance and to induce apoptosis through Ca²⁺-dependent induction of endoplasmic reticulum stress, changes in the expression of selenoproteins and selenium-containing proteins, as well as key kinases-regulators of oncogenicity and cell death. Selenium nanoparticles (SeNPs) also have a high anticancer efficacy in glioblastomas, but are less selective, since SeSo in cortical astrocytes causes a more pronounced activation of the cytoprotective pathways. Full article

(This article belongs to the Special Issue Calcium Signaling in Mammalian Cells: From Physiology to Pathology)

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28 pages, 6269 KiB

Open AccessArticle

Novel Algorithm of Network Calcium Dynamics Analysis for Studying the Role of Astrocytes in Neuronal Activity in Alzheimer’s Disease Models

by Elena V. Mitroshina, Alexander M. Pakhomov, Mikhail I. Krivonosov, Roman S. Yarkov, Maria S. Gavrish, Alexey V. Shkirin, Mikhail V. Ivanchenko and Maria V. Vedunova

Int. J. Mol. Sci. 2022, 23(24), 15928; https://doi.org/10.3390/ijms232415928 - 14 Dec 2022

Cited by 8 | Viewed by 2404

Abstract

Accumulated experimental data strongly suggest that astrocytes play an important role in the pathogenesis of neurodegeneration, including Alzheimer’s disease (AD). The effect of astrocytes on the calcium activity of neuron–astroglia networks in AD modelling was the object of the present study. We have expanded and improved our approach’s capabilities to analyze calcium activity. We have developed a novel algorithm to construct dynamic directed graphs of both astrocytic and neuronal networks. The proposed algorithm allows us not only to identify functional relationships between cells and determine the presence of network activity, but also to characterize the spread of the calcium signal from cell to cell. Our study showed that Alzheimer’s astrocytes can change the functional pattern of the calcium activity of healthy nerve cells. When healthy nerve cells were cocultivated with astrocytes treated with Aβ42, activation of calcium signaling was found. When healthy nerve cells were cocultivated with 5xFAD astrocytes, inhibition of calcium signaling was observed. In this regard, it seems relevant to further study astrocytic–neuronal interactions as an important factor in the regulation of the functional activity of brain cells during neurodegenerative processes. The approach to the analysis of streaming imaging data developed by the authors is a promising tool for studying the collective calcium dynamics of nerve cells. Full article

(This article belongs to the Special Issue Calcium Signaling in Mammalian Cells: From Physiology to Pathology)

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Review

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22 pages, 1947 KiB

Open AccessReview

The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives

by Teresa Soda, Valentina Brunetti, Roberto Berra-Romani and Francesco Moccia

Int. J. Mol. Sci. 2023, 24(4), 3914; https://doi.org/10.3390/ijms24043914 - 15 Feb 2023

Cited by 23 | Viewed by 7653

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate, mediate the slow component of excitatory neurotransmission in the central nervous system (CNS), and induce long-term changes in synaptic plasticity. NMDARs are non-selective cation channels that allow the influx of extracellular Na⁺ and Ca²⁺ and control cellular activity via both membrane depolarization and an increase in intracellular Ca²⁺ concentration. The distribution, structure, and role of neuronal NMDARs have been extensively investigated and it is now known that they also regulate crucial functions in the non-neuronal cellular component of the CNS, i.e., astrocytes and cerebrovascular endothelial cells. In addition, NMDARs are expressed in multiple peripheral organs, including heart and systemic and pulmonary circulations. Herein, we survey the most recent information available regarding the distribution and function of NMDARs within the cardiovascular system. We describe the involvement of NMDARs in the modulation of heart rate and cardiac rhythm, in the regulation of arterial blood pressure, in the regulation of cerebral blood flow, and in the blood–brain barrier (BBB) permeability. In parallel, we describe how enhanced NMDAR activity could promote ventricular arrhythmias, heart failure, pulmonary artery hypertension (PAH), and BBB dysfunction. Targeting NMDARs could represent an unexpected pharmacological strategy to reduce the growing burden of several life-threatening cardiovascular disorders. Full article

(This article belongs to the Special Issue Calcium Signaling in Mammalian Cells: From Physiology to Pathology)

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