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Biomolecules
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Dysregulation of Calcium Signaling in Pathological Processes
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Dysregulation of Calcium Signaling in Pathological Processes

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (30 November 2024) | Viewed by 16870

Special Issue Editor

Prof. Dr. Antonio Villalobo

E-Mail Website1 Website2
Guest Editor
Instituto de Investigaciones Sanitarias (IdiPAZ), Hospital Universitario La Paz, Madrid, Spain
Interests: calcium; calmodulin; cancer; receptor tyrosine kinases EGFR/ErbB1/HER1 and ErbB2/HER2; adaptor protein Grb7; and non-receptor tyrosine kinase Src
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Calcium-mediated signaling in eukaryotic cells is an universal mechanism controlling a myriad of cellular processes. In a significant number of human pathologies, the dysregulation of Ca2+ signaling and Ca2+-mediated control systems implicated in diverse cellular functions have been observed. This Special Issue collects reviews and research articles describing a variety of alterations in human pathologies occurring in the toolkit used by the cells to handle Ca2+ signaling, including potentially important and already observed or newly suspected dysregulations of Ca2+ signaling in the followings illnesses, among others: cardiovascular diseases (e.g., heart arrhythmias and hypertrophy); muscle diseases (e.g., muscular dystrophies); neurodegenerative processes (e.g., Alzheimer disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington disease, Lewy body dementia, frontotemporal dementia, Parkinson disease, and spinal muscular atrophy, among others); endocrine diseases (e.g., diabetes, and hypothalamus, pituitary, thyroid, adrenal, and other endocrine glands disorders); autoimmune diseases (e.g., multiple sclerosis, lupus erythematosus, Graves disease, among many others); and solid tumors and hematological cancers (leukemias and lymphomas). Finally, it will also consider diseases associated with failure in mitochondrial Ca2+ movement (e.g., Ca2+ uniport channel mutations); mutations of Ca2+-binding proteins (e.g., CaM, resulting in so-called calmodulinopathies, and troponin C, resulting in hypertrophic cardiomyopathies); mutations of Ca2+ channels (resulting in so-called channelopathies); and mutations of Ca2+ transporters (e.g., sarcoplasmic reticulum Ca2+-ATPase [SERCA], resulting in Darier disease, and plasma membrane Ca2+-ATPase [PMCA], resulting in Hailey–Hailey disease).

Kind regards,

Prof. Dr. Antonio Villalobo
Guest Editor

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Keywords

  • Ca2+-ATPases
  • calmodulinopathies
  • cancer
  • cardiovascular diseases
  • channelopathies
  • endocrine diseases
  • mitochondrial diseases
  • muscle diseases
  • neurodegenerative diseases
  • troponin C

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Published Papers (7 papers)

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22 pages, 3998 KiB  
Article
Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
by Kasope Wolffs, Renjiao Li, Bethan Mansfield, Daniel A. Pass, Richard T. Bruce, Ping Huang, Rachel Paes de Araújo, Bahareh Sadat Haddadi, Luis A. J. Mur, Jordanna Dally, Ryan Moseley, Rupert Ecker, Harry Karmouty-Quintana, Keir E. Lewis, A. John Simpson, Jeremy P. T. Ward, Christopher J. Corrigan, Renata Z. Jurkowska, Benjamin D. Hope-Gill, Daniela Riccardi and Polina L. Yarovaadd Show full author list remove Hide full author list
Biomolecules 2025, 15(4), 509; https://doi.org/10.3390/biom15040509 - 1 Apr 2025
Viewed by 508
Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and no curative therapies. Fibroblast activation by transforming growth factor β1 (TGFβ1) and disrupted metabolic pathways, including the arginine–polyamine pathway, play crucial roles in IPF development. Polyamines are agonists of the calcium/cation-sensing [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and no curative therapies. Fibroblast activation by transforming growth factor β1 (TGFβ1) and disrupted metabolic pathways, including the arginine–polyamine pathway, play crucial roles in IPF development. Polyamines are agonists of the calcium/cation-sensing receptor (CaSR), activation of which is detrimental for asthma and pulmonary hypertension, but its role in IPF is unknown. To address this question, we evaluated polyamine abundance using metabolomic analysis of IPF patient saliva. Furthermore, we examined CaSR functional expression in human lung fibroblasts (HLFs), assessed the anti-fibrotic effects of a CaSR antagonist, NPS2143, in TGFβ1-activated normal and IPF HLFs by RNA sequencing and immunofluorescence imaging, respectively; and NPS2143 effects on polyamine synthesis in HLFs by immunoassays. Our results demonstrate that polyamine metabolites are increased in IPF patient saliva. Polyamines activate fibroblast CaSR in vitro, elevating intracellular calcium concentration. CaSR inhibition reduced TGFβ1-induced polyamine and pro-fibrotic factor expression in normal and IPF HLFs. TGFβ1 directly stimulated polyamine release by HLFs, an effect that was blocked by NPS2143. This suggests that TGFβ1 promotes CaSR activation through increased polyamine expression, driving a pro-fibrotic response. By halting some polyamine-induced pro-fibrotic changes, CaSR antagonists exhibit disease-modifying potential in IPF onset and development. Full article
(This article belongs to the Special Issue Dysregulation of Calcium Signaling in Pathological Processes)
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Review

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23 pages, 8721 KiB  
Review
The Physiological Functions and Therapeutic Potential of Hypoxia-Inducible Factor-1α in Vascular Calcification
by Zhenghong Zhang, Defan Wang, Renfeng Xu, Xiang Li, Zhengchao Wang and Yang Zhang
Biomolecules 2024, 14(12), 1592; https://doi.org/10.3390/biom14121592 - 12 Dec 2024
Cited by 1 | Viewed by 1526
Abstract
HIF-1α plays a crucial regulatory role in vascular calcification (VC), primarily influencing the osteogenic differentiation of VSMCs through oxygen-sensing mechanisms. Under hypoxic conditions, the stability of HIF-1α increases, avoiding PHD and VHL protein-mediated degradation, which promotes its accumulation in cells and then activates [...] Read more.
HIF-1α plays a crucial regulatory role in vascular calcification (VC), primarily influencing the osteogenic differentiation of VSMCs through oxygen-sensing mechanisms. Under hypoxic conditions, the stability of HIF-1α increases, avoiding PHD and VHL protein-mediated degradation, which promotes its accumulation in cells and then activates gene expressions related to calcification. Additionally, HIF-1α modulates the metabolic state of VSMCs by regulating the pathways that govern the switch between glycolysis and oxidative phosphorylation, thereby further advancing the calcification process. The interaction between HIF-1α and other signaling pathways, such as nuclear factor-κB, Notch, and Wnt/β-catenin, creates a complex regulatory network that serves as a critical driving force in VC. Therefore, a deeper understanding of the role and regulatory mechanism of the HIF-1α signaling during the development and progression of VC is of great significance, as it is not only a key molecular marker for understanding the pathological mechanisms of VC but also represents a promising target for future anti-calcification therapies. Full article
(This article belongs to the Special Issue Dysregulation of Calcium Signaling in Pathological Processes)
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20 pages, 2940 KiB  
Review
Unmasking the Mechanism behind Miltefosine: Revealing the Disruption of Intracellular Ca2+ Homeostasis as a Rational Therapeutic Target in Leishmaniasis and Chagas Disease
by Gustavo Benaim and Alberto Paniz-Mondolfi
Biomolecules 2024, 14(4), 406; https://doi.org/10.3390/biom14040406 - 27 Mar 2024
Cited by 10 | Viewed by 3331
Abstract
Originally developed as a chemotherapeutic agent, miltefosine (hexadecylphosphocholine) is an inhibitor of phosphatidylcholine synthesis with proven antiparasitic effects. It is the only oral drug approved for the treatment of Leishmaniasis and American Trypanosomiasis (Chagas disease). Although its precise mechanisms are not yet fully [...] Read more.
Originally developed as a chemotherapeutic agent, miltefosine (hexadecylphosphocholine) is an inhibitor of phosphatidylcholine synthesis with proven antiparasitic effects. It is the only oral drug approved for the treatment of Leishmaniasis and American Trypanosomiasis (Chagas disease). Although its precise mechanisms are not yet fully understood, miltefosine exhibits broad-spectrum anti-parasitic effects primarily by disrupting the intracellular Ca2+ homeostasis of the parasites while sparing the human hosts. In addition to its inhibitory effects on phosphatidylcholine synthesis and cytochrome c oxidase, miltefosine has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites. Both of these crucial organelles are involved in Ca2+ regulation. Furthermore, miltefosine has the ability to activate a specific parasite Ca2+ channel that responds to sphingosine, which is different to its L-type VGCC human ortholog. Here, we aimed to provide an overview of recent advancements of the anti-parasitic mechanisms of miltefosine. We also explored its multiple molecular targets and investigated how its pleiotropic effects translate into a rational therapeutic approach for patients afflicted by Leishmaniasis and American Trypanosomiasis. Notably, miltefosine’s therapeutic effect extends beyond its impact on the parasite to also positively affect the host’s immune system. These findings enhance our understanding on its multi-targeted mechanism of action. Overall, this review sheds light on the intricate molecular actions of miltefosine, highlighting its potential as a promising therapeutic option against these debilitating parasitic diseases. Full article
(This article belongs to the Special Issue Dysregulation of Calcium Signaling in Pathological Processes)
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22 pages, 1241 KiB  
Review
Calcium-Associated Proteins in Neuroregeneration
by Malwina Lisek, Julia Tomczak, Tomasz Boczek and Ludmila Zylinska
Biomolecules 2024, 14(2), 183; https://doi.org/10.3390/biom14020183 - 2 Feb 2024
Cited by 11 | Viewed by 2997
Abstract
The dysregulation of intracellular calcium levels is a critical factor in neurodegeneration, leading to the aberrant activation of calcium-dependent processes and, ultimately, cell death. Ca2+ signals vary in magnitude, duration, and the type of neuron affected. A moderate Ca2+ concentration can [...] Read more.
The dysregulation of intracellular calcium levels is a critical factor in neurodegeneration, leading to the aberrant activation of calcium-dependent processes and, ultimately, cell death. Ca2+ signals vary in magnitude, duration, and the type of neuron affected. A moderate Ca2+ concentration can initiate certain cellular repair pathways and promote neuroregeneration. While the peripheral nervous system exhibits an intrinsic regenerative capability, the central nervous system has limited self-repair potential. There is evidence that significant variations exist in evoked calcium responses and axonal regeneration among neurons, and individual differences in regenerative capacity are apparent even within the same type of neurons. Furthermore, some studies have shown that neuronal activity could serve as a potent regulator of this process. The spatio-temporal patterns of calcium dynamics are intricately controlled by a variety of proteins, including channels, ion pumps, enzymes, and various calcium-binding proteins, each of which can exert either positive or negative effects on neural repair, depending on the cellular context. In this concise review, we focus on several calcium-associated proteins such as CaM kinase II, GAP-43, oncomodulin, caldendrin, calneuron, and NCS-1 in order to elaborate on their roles in the intrinsic mechanisms governing neuronal regeneration following traumatic damage processes. Full article
(This article belongs to the Special Issue Dysregulation of Calcium Signaling in Pathological Processes)
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20 pages, 1473 KiB  
Review
The Complex Interplay between Toxic Hallmark Proteins, Calmodulin-Binding Proteins, Ion Channels, and Receptors Involved in Calcium Dyshomeostasis in Neurodegeneration
by Danton H. O’Day
Biomolecules 2024, 14(2), 173; https://doi.org/10.3390/biom14020173 - 31 Jan 2024
Cited by 6 | Viewed by 2234
Abstract
Calcium dyshomeostasis is an early critical event in neurodegeneration as exemplified by Alzheimer’s (AD), Huntington’s (HD) and Parkinson’s (PD) diseases. Neuronal calcium homeostasis is maintained by a diversity of ion channels, buffers, calcium-binding protein effectors, and intracellular storage in the endoplasmic reticulum, mitochondria, [...] Read more.
Calcium dyshomeostasis is an early critical event in neurodegeneration as exemplified by Alzheimer’s (AD), Huntington’s (HD) and Parkinson’s (PD) diseases. Neuronal calcium homeostasis is maintained by a diversity of ion channels, buffers, calcium-binding protein effectors, and intracellular storage in the endoplasmic reticulum, mitochondria, and lysosomes. The function of these components and compartments is impacted by the toxic hallmark proteins of AD (amyloid beta and Tau), HD (huntingtin) and PD (alpha-synuclein) as well as by interactions with downstream calcium-binding proteins, especially calmodulin. Each of the toxic hallmark proteins (amyloid beta, Tau, huntingtin, and alpha-synuclein) binds to calmodulin. Multiple channels and receptors involved in calcium homeostasis and dysregulation also bind to and are regulated by calmodulin. The primary goal of this review is to show the complexity of these interactions and how they can impact research and the search for therapies. A secondary goal is to suggest that therapeutic targets downstream from calcium dyshomeostasis may offer greater opportunities for success. Full article
(This article belongs to the Special Issue Dysregulation of Calcium Signaling in Pathological Processes)
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24 pages, 7675 KiB  
Review
Ca2+ Signaling and Src Functions in Tumor Cells
by Antonio Villalobo
Biomolecules 2023, 13(12), 1739; https://doi.org/10.3390/biom13121739 - 3 Dec 2023
Cited by 7 | Viewed by 2631
Abstract
Signaling by calcium ion (Ca2+) plays a prominent role in cell physiology, and these mechanisms are frequently altered in tumor cells. In this review, we consider the interplay of Ca2+ signaling and the functions of the proto-oncogene non-receptor tyrosine kinase [...] Read more.
Signaling by calcium ion (Ca2+) plays a prominent role in cell physiology, and these mechanisms are frequently altered in tumor cells. In this review, we consider the interplay of Ca2+ signaling and the functions of the proto-oncogene non-receptor tyrosine kinase c-Src in tumor cells, and the viral oncogenic variant v-Src in transformed cells. Also, other members of the Src-family kinases are considered in this context. The role of Ca2+ in the cell is frequently mediated by Ca2+-binding proteins, where the Ca2+-sensor protein calmodulin (CaM) plays a prominent, essential role in many cellular signaling pathways. Thus, we cover the available information on the role and direct interaction of CaM with c-Src and v-Src in cancerous cells, the phosphorylation of CaM by v-Src/c-Src, and the actions of different CaM-regulated Ser/Thr-protein kinases and the CaM-dependent phosphatase calcineurin on v-Src/c-Src. Finally, we mention some clinical implications of these systems to identify mechanisms that could be targeted for the therapeutic treatment of human cancers. Full article
(This article belongs to the Special Issue Dysregulation of Calcium Signaling in Pathological Processes)
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14 pages, 849 KiB  
Review
The Ca2+ Sensor STIM in Human Diseases
by Alejandro Berna-Erro, Jose Sanchez-Collado, Joel Nieto-Felipe, Alvaro Macias-Diaz, Pedro C. Redondo, Tarik Smani, Jose J. Lopez, Isaac Jardin and Juan A. Rosado
Biomolecules 2023, 13(9), 1284; https://doi.org/10.3390/biom13091284 - 22 Aug 2023
Cited by 7 | Viewed by 2493
Abstract
The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca2+ entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins [...] Read more.
The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca2+ entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca2+ sensors in the endoplasmic reticulum (ER) and, upon Ca2+ store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca2+ signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca2+ signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects. Full article
(This article belongs to the Special Issue Dysregulation of Calcium Signaling in Pathological Processes)
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