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Calcium Homeostasis of Cells in Health and Disease: 2nd Edition

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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 April 2025) | Viewed by 12143

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Dr. Péter Szentesi

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Department of Physiology, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98., H-4002 Debrecen, Hungary
Interests: skeletal muscle; intracellular calcium; excitation contraction coupling; muscle force; myopathies; aging; antioxidants
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Prof. Dr. László Csernoch

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Department of Physiology, Medical Faculty, University of Debrecen, H-4002 Debrecen, Hungary
Interests: calcium signaling; skeletal muscle; excitation-contraction coupling
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Calcium Homeostasis of Cells in Health and Disease”.

Whether in health or in disease, calcium ion (Ca²⁺) plays a very important role in stimulus–answers processes of cells as a second messenger. This works by retaining intracellular Ca²⁺ concentration low at rest and by mobilizing Ca²⁺ in answer to stimuli, which activates cellular functions. This second messenger role of Ca²⁺ was first discovered in excitation–contraction coupling of skeletal muscle. Later on, the characteristics of Ca²⁺ as a second messenger, the variety of targets, its ability to achieve quick and enormous transient and also oscillatory mobilization, and the capability of causing localized and also generalized cell responses were studied widely.

Although calcium is extensively studied in a variety of cells, there are a lot of features which are still uncertain: what is its role in physiological and in pathological circumstances? Quite a few studies have shown that the Ca²⁺ homeostasis of cells is modified during development and while they are getting old. The latter becomes more and more important as the Earth’s population reaches an increasingly old age. Thus, aging is one of the hot topics in human research. However, alteration in calcium homeostasis can occur not only in old age but in several diseases. In addition, new technological challenges and innovations on the use of calcium sensors appear from time to time and open new possibilities to deepen our knowledge in studying calcium concentration outside and inside of the cells or even in cell organelles.

The aim of the present Special Issue is to collect novel data regarding the role of calcium in the functions of cells. We specifically encourage the submission of manuscripts presenting innovative approaches to identify novel strategies to maintain and/or improve cell functions in aging and in diseases.

Dr. Péter Szentesi
Prof. Dr. László Csernoch
Guest Editors

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Keywords

Ca²⁺
calcium homeostasis
calcium-binding proteins
aging
disease

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Calcium Homeostasis of Cells in Health and Disease in International Journal of Molecular Sciences (15 articles)

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Research

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16 pages, 2847 KiB

Open AccessArticle

Calcium Homeostasis Disrupted—How Store-Operated Calcium Entry Factor SARAF Silencing Impacts HepG2 Liver Cancer Cells

by Safa Taha, Muna Aljishi, Ameera Sultan and Moiz Bakhiet

Int. J. Mol. Sci. 2025, 26(9), 4426; https://doi.org/10.3390/ijms26094426 - 7 May 2025

Viewed by 226

Abstract

Hepatocellular carcinoma (HCC), a highly aggressive liver malignancy, is often associated with disrupted calcium homeostasis. Store-operated calcium entry (SOCE), involving components such as STIM1, Orai1, and SARAF, plays a critical role in calcium signaling and cancer progression. While STIM1 and Orai1 have been extensively studied, SARAF’s role as a negative regulator of SOCE in HCC remains poorly understood. This preliminary study investigated SARAF’s effects on calcium homeostasis, proliferation, and migration in HepG2 liver cancer cells, providing initial evidence of its tumor-suppressive role. SARAF expression was modulated using siRNA knockdown and overexpression plasmids, with validation by qRT-PCR. Functional assays demonstrated that SARAF silencing increased proliferation by 50% and migration by 40% (p < 0.05), while SARAF overexpression reduced proliferation by 50% and migration by 45% (p < 0.01), highlighting its tumor-suppressive role. Intracellular calcium levels, elevated in HepG2 cells, were partially restored by SARAF overexpression, though SARAF silencing did not further disrupt calcium regulation. These findings suggest that SARAF negatively regulates proliferation and migration in HCC, potentially through its role in maintaining calcium homeostasis. SARAF represents a promising therapeutic target in HCC. Future studies should explore the downstream molecular mechanisms governing SARAF’s effects, investigate its role in other cancers, and assess its clinical potential for liver cancer therapy. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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27 pages, 2245 KiB

Open AccessArticle

T Lymphocyte Integrated Endoplasmic Reticulum Ca²⁺ Store Signaling Functions Are Linked to Sarco/Endoplasmic Reticulum Ca²⁺-ATPase Isoform-Specific Levels of Regulation

by Md Nasim Uddin and David W. Thomas

Int. J. Mol. Sci. 2025, 26(9), 4147; https://doi.org/10.3390/ijms26094147 - 27 Apr 2025

Viewed by 297

Abstract

We explored the effects of altering expression levels of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) ion-transporting enzymes on key T lymphocyte signaling functions. In these studies, we have taken advantage of the Jurkat T cell line which provides a T lymphocyte model cell phenotype with a well-characterized T cell receptor (TCR)-activated signaling pathway, as well as offering a cellular system with a good understanding of the SERCA expression profile. These studies have been prompted by a strong imperative to gain a better understanding of the complex roles SERCA Ca²⁺ pumps play in the integrated TCR-activated signaling network, particularly given the central role of SERCA functions in regulating essential endoplasmic reticulum (ER) integrity. We find in this study that altering SERCA expression can significantly reconfigure ER Ca²⁺ stores, increasing or decreasing Ca²⁺ storage capacity depending on upregulation or downregulation of SERCA expression, and these effects are also associated with substantial changes in agonist-induced Ca²⁺ release and influx patterns. Not surprisingly, these fundamental changes in TCR-regulated Ca²⁺ signaling properties are associated with major alterations in T lymphocyte functions including regulation of growth patterns, cytokine secretion and energy utilization. Our study also describes additional evidence revealing intriguing functional distinctions between the major SERCA isoform-regulated Ca²⁺ stores in T lymphocytes. Our work thus serves to reinforce increasing efforts to target the SERCA pumps as a potential profitable strategy to produce novel engineered T lymphocytes in the rapidly growing field of T-cell immunotherapy Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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19 pages, 1338 KiB

Open AccessArticle

Activation of Small Conductance Ca²⁺-Activated K⁺ Channels Suppresses Electrical and Calcium Alternans in Atrial Myocytes

by Giedrius Kanaporis and Lothar A. Blatter

Int. J. Mol. Sci. 2025, 26(8), 3597; https://doi.org/10.3390/ijms26083597 - 11 Apr 2025

Viewed by 382

Abstract

Small conductance Ca²⁺-activated K⁺ (SK) channels are expressed in atria and ventricles. However, the data on the contribution of SK channels to atrial action potential (AP) repolarization are inconsistent. We investigated the effect of SK channel modulators on AP morphology in rabbit atrial myocytes and tested the hypothesis that pharmacological activation of SK channels suppresses pacing-induced Ca²⁺ transient (CaT) and AP duration (APD) alternans. At the cellular level, alternans are observed as beat-to-beat alternations in contraction, APD, and CaT amplitude, representing a risk factor for arrhythmias, including atrial fibrillation. Our results show that SK channel inhibition by apamin did not affect atrial APD under basal conditions. However, SK channel activation by NS309 significantly shortened APD, indicating the expression of functional SK channels. Moreover, the activation of SK channels reduced CaT amplitude and sarcoplasmic reticulum Ca²⁺ load. Activation of SK channels also suppressed pacing-induced CaT and APD alternans. K_V7.1 potassium channel inhibition, simulating long QT syndrome type-1 conditions, increased the risk of atrial CaT alternans, which was abolished by the activation of SK channels. In summary, our data suggest that pharmacological modulation of SK channels can potentially reduce atrial arrhythmia risk arising from pathological APD prolongation. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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25 pages, 1878 KiB

Open AccessArticle

Calcium Signaling Is a Universal Carbon Source Signal Transducer and Effects an Ionic Memory of Past Carbon Sources

by Kobi Simpson-Lavy and Martin Kupiec

Int. J. Mol. Sci. 2025, 26(5), 2198; https://doi.org/10.3390/ijms26052198 - 28 Feb 2025

Viewed by 356

Abstract

Glucose is the preferred carbon source for most cells. However, cells may encounter other carbon sources that can be utilized. How cells match their metabolic gene expression to their carbon source, beyond a general glucose repressive system (catabolite repression), remains little understood. By studying the effect of up to seven different carbon sources on Snf1 phosphorylation and on the expression of downstream regulated genes, we searched for the mechanism that identifies carbon sources. We found that the glycolysis metabolites glucose-6-phosphate (G6P) and glucose-1-phosphate (G1P) play a central role in the adaptation of gene expression to different carbon sources. The ratio of G1P and G6P activates analogue calcium signaling via the proton-exporter Pma1 to regulate downstream genes. The signaling pathway bifurcates with calcineurin-reducing ADH2 (alcohol dehydrogenase) expression and with Cmk1-increasing ZWF1 (glucose-6-phosphate dehydrogenase) expression. Furthermore, calcium signaling is not only regulated by the present carbon source; it is also regulated by past carbon sources. We were able to manipulate this ionic memory mechanism to obtain high expression of ZWF1 in media containing galactose. Our findings provide a universal mechanism by which cells respond to all carbon sources. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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11 pages, 1664 KiB

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Aging Favors Calcium Activation of Ryanodine Receptor Channels from Brain Cortices and Hippocampi and Hinders Learning and Memory in Male Rats

by Jamileth More, José Pablo Finkelstein, José Luis Valdés, Cecilia Hidalgo and Ricardo Bull

Int. J. Mol. Sci. 2025, 26(5), 2101; https://doi.org/10.3390/ijms26052101 - 27 Feb 2025

Viewed by 342

Abstract

The response of ryanodine receptor (RyR) channels to increases in free cytoplasmic calcium concentration ([Ca²⁺]) is tuned by several mechanisms, including redox signaling. Three different responses to [Ca²⁺] have been described in RyR channels, low, moderate and high activity responses, which depend on the RyR channel protein oxidation state. Thus, reduced RyR channels display the low activity response, whereas partially oxidized channels display the moderate response and more oxidized channels, the high activity response. As described here, RyR channels from rat brain cortices or hippocampi displayed aged-related marked changes in the distribution of these channel responses; RyR channels from aged rats displayed reduced fraction of low activity channels and increased fraction of high activity channels, which would favor Ca²⁺-induced Ca²⁺ release. In addition, compared with young rats, aged rats displayed learning and memory defects, with lower hit rates when tested in the Oasis maze, a dry version of the Morris water maze. Previous oral administration of N-acetylcysteine for 3 weeks prevented both the age-dependent effects on RyR channel activation by [Ca²⁺], and the learning and memory defects. Based on these results, it is proposed that redox-sensitive neuronal RyR channels partake in the mechanism underlying the learning and memory disruptions displayed by aged rats. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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14 pages, 3938 KiB

Open AccessArticle

The Rise in Tubular pH during Hypercalciuria Exacerbates Calcium Stone Formation

by Farai C. Gombedza, Samuel Shin, Jaclyn Sadiua, George B. Stackhouse and Bidhan C. Bandyopadhyay

Int. J. Mol. Sci. 2024, 25(9), 4787; https://doi.org/10.3390/ijms25094787 - 27 Apr 2024

Cited by 2 | Viewed by 1493

Abstract

In calcium nephrolithiasis (CaNL), most calcium kidney stones are identified as calcium oxalate (CaOx) with variable amounts of calcium phosphate (CaP), where CaP is found as the core component. The nucleation of CaP could be the first step of CaP+CaOx (mixed) stone formation. High urinary supersaturation of CaP due to hypercalciuria and an elevated urine pH have been described as the two main factors in the nucleation of CaP crystals. Our previous in vivo findings (in mice) show that transient receptor potential canonical type 3 (TRPC3)-mediated Ca²⁺ entry triggers a transepithelial Ca²⁺ flux to regulate proximal tubular (PT) luminal [Ca²⁺], and TRPC3-knockout (KO; -/-) mice exhibited moderate hypercalciuria and microcrystal formation at the loop of Henle (LOH). Therefore, we utilized TRPC3 KO mice and exposed them to both hypercalciuric [2% calcium gluconate (CaG) treatment] and alkalineuric conditions [0.08% acetazolamide (ACZ) treatment] to generate a CaNL phenotype. Our results revealed a significant CaP and mixed crystal formation in those treated KO mice (KOT) compared to their WT counterparts (WTT). Importantly, prolonged exposure to CaG and ACZ resulted in a further increase in crystal size for both treated groups (WTT and KOT), but the KOT mice crystal sizes were markedly larger. Moreover, kidney tissue sections of the KOT mice displayed a greater CaP and mixed microcrystal formation than the kidney sections of the WTT group, specifically in the outer and inner medullary and calyceal region; thus, a higher degree of calcifications and mixed calcium lithiasis in the kidneys of the KOT group was displayed. In our effort to find the Ca²⁺ signaling pathophysiology of PT cells, we found that PT cells from both treated groups (WTT and KOT) elicited a larger Ca²⁺ entry compared to the WT counterparts because of significant inhibition by the store-operated Ca²⁺ entry (SOCE) inhibitor, Pyr6. In the presence of both SOCE (Pyr6) and ROCE (receptor-operated Ca²⁺ entry) inhibitors (Pyr10), Ca²⁺ entry by WTT cells was moderately inhibited, suggesting that the Ca²⁺ and pH levels exerted sensitivity changes in response to ROCE and SOCE. An assessment of the gene expression profiles in the PT cells of WTT and KOT mice revealed a safeguarding effect of TRPC3 against detrimental processes (calcification, fibrosis, inflammation, and apoptosis) in the presence of higher pH and hypercalciuric conditions in mice. Together, these findings show that compromise in both the ROCE and SOCE mechanisms in the absence of TRPC3 under hypercalciuric plus higher tubular pH conditions results in higher CaP and mixed crystal formation and that TRPC3 is protective against those adverse effects. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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12 pages, 2443 KiB

Open AccessArticle

Vaping-Dependent Pulmonary Inflammation Is Ca²⁺ Mediated and Potentially Sex Specific

by Jeffrey G. Shipman, Rob U. Onyenwoke and Vijay Sivaraman

Int. J. Mol. Sci. 2024, 25(3), 1785; https://doi.org/10.3390/ijms25031785 - 1 Feb 2024

Cited by 1 | Viewed by 2639

Abstract

Here we use the SCIREQ InExpose system to simulate a biologically relevant vaping model in mice to investigate the role of calcium signaling in vape-dependent pulmonary disease as well as to investigate if there is a gender-based difference of disease. Male and female mice were vaped with JUUL Menthol (3% nicotine) using the SCIREQ InExpose system for 2 weeks. Additionally, 2-APB, a known calcium signaling inhibitor, was administered as a prophylactic for lung disease and damage caused by vaping. After 2 weeks, mice were exposed to lipopolysaccharide (LPS) to mimic a bacterial infection. Post-infection (24 h), mice were sacrificed, and bronchoalveolar lavage fluid (BALF) and lungs were taken. Vaping primed the lungs for worsened disease burden after microbial challenge (LPS) for both males and females, though females presented increased neutrophilia and inflammatory cytokines post-vape compared to males, which was assessed by flow cytometry, and cytokine and histopathological analysis. This increased inflammatory burden was controlled by calcium signaling inhibition, suggesting that calcium dysregulation may play a role in lung injury caused by vaping in a gender-dependent manner. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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Review

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31 pages, 1545 KiB

Open AccessReview

Astrocytes in Rodent Anxiety-Related Behavior: Role of Calcium and Beyond

by Marta Gómez-Gonzalo

Int. J. Mol. Sci. 2025, 26(6), 2774; https://doi.org/10.3390/ijms26062774 - 19 Mar 2025

Viewed by 556

Abstract

Anxiety is a physiological, emotional response that anticipates distal threats. When kept under control, anxiety is a beneficial response, helping animals to maintain heightened attention in environments with potential dangers. However, an overestimation of potential threats can lead to an excessive expression of anxiety that, in humans, may evolve into anxiety disorders. Pharmacological treatments show variable efficacy among patients, highlighting the need for more efforts to better understand the pathogenesis of anxiety disorders. Mounting evidence suggests that astrocytes, a type of glial cells, are active partners of neurons in brain circuits and in the regulation of behaviors under both physiological and pathological conditions. In this review, I summarize the current literature on the role of astrocytes from different brain regions in modulating anxious states, with the goal of exploring novel cerebral mechanisms to identify potential innovative therapeutic targets for the treatment of anxiety disorders. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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24 pages, 2416 KiB

Open AccessReview

Calcium Ions in the Physiology and Pathology of the Central Nervous System

by Damian Pikor, Mikołaj Hurła, Bartosz Słowikowski, Oliwia Szymanowicz, Joanna Poszwa, Natalia Banaszek, Alicja Drelichowska, Paweł P. Jagodziński, Wojciech Kozubski and Jolanta Dorszewska

Int. J. Mol. Sci. 2024, 25(23), 13133; https://doi.org/10.3390/ijms252313133 - 6 Dec 2024

Cited by 6 | Viewed by 4671

Abstract

Calcium ions play a key role in the physiological processes of the central nervous system. The intracellular calcium signal, in nerve cells, is part of the neurotransmission mechanism. They are responsible for stabilizing membrane potential and controlling the excitability of neurons. Calcium ions are a universal second messenger that participates in depolarizing signal transduction and contributes to synaptic activity. These ions take an active part in the mechanisms related to memory and learning. As a result of depolarization of the plasma membrane or stimulation of receptors, there is an extracellular influx of calcium ions into the cytosol or mobilization of these cations inside the cell, which increases the concentration of these ions in neurons. The influx of calcium ions into neurons occurs via plasma membrane receptors and voltage-dependent ion channels. Calcium channels play a key role in the functioning of the nervous system, regulating, among others, neuronal depolarization and neurotransmitter release. Channelopathies are groups of diseases resulting from mutations in genes encoding ion channel subunits, observed including the pathophysiology of neurological diseases such as migraine. A disturbed ability of neurons to maintain an appropriate level of calcium ions is also observed in such neurodegenerative processes as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and epilepsy. This review focuses on the involvement of calcium ions in physiological and pathological processes of the central nervous system. We also consider the use of calcium ions as a target for pharmacotherapy in the future. Full article

(This article belongs to the Special Issue Calcium Homeostasis of Cells in Health and Disease: 2nd Edition)

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