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Special Issue "Calcium Signaling in Human Health and Diseases 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 August 2019).

Special Issue Editor

Dr. Francesco Moccia
E-Mail Website
Guest Editor
Laboratory of General Physiology, Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy
Interests: Ca2+ signaling; angiogenesis; endothelial cells; endothelial progenitor cells; neurovascular coupling
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue "Calcium Signaling in Human Health and Diseases" (https://www.mdpi.com/journal/ijms/special_issues/calcium_signaling).

Intracellular Ca2+ signals regulate a myriad of cellular functions, ranging from short-term responses, such as excitation–contraction coupling and stimulus–secretion coupling, to long-term processes, such as proliferation, gene expression, differentiation, motility, synaptic plasticity, programmed cell death (or apoptosis) and metabolism. It is, therefore, not surprising that any derangement of the multifaceted Ca2+ toolkit that shapes the elevation in intracellular Ca2+ concentration ([Ca2+]i) may lead to severe pathological disorders, including cancer, neurodegenerative diseases, heart failure, severe combined immunodeficiency (SCID), deafness, pancreatitis, hypertension, and so on. An increase in [Ca2+]i is shaped by the concerted interaction among the components of an extremely versatile network of channels, transporters, pumps and buffer that can be uniquely assembled by each cell type to generate intracellular Ca2+ signals with spatio-temporal properties precisely tailored to regulate specific functions. We are witnessing a fascinating period of ground-breaking discoveries in the Ca2+ signalling field, as testified by the identification of the first structural molecular components of the mitochondrial Ca2+ uniporter and permeability transition pore, by the discovery of many unexpected regulators of intracellular Ca2+ dynamics, such as p53, PML, and PTEN, and by the evidence that a growing number of pathologies is associated to mutations in Ca2+-permeable channels and/or Ca2+-regulated pathways. I am, therefore, pleased to invite all of you to participate to this Special Issue, "Calcium Signaling in Human Health and Diseases", by presenting your most recent research or ideas about the pathophysiological role of Ca2+. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Dr. Francesco Moccia
Guest Editor

Manuscript Submission Information

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Keywords

  • Ca2+ signalling
  • intracellular organelles
  • plasma membrane
  • inositol-1,4,5-receptors
  • ryanodine receptors
  • ionotropic receptors
  • metabotropic receptors
  • TRP channels
  • two-pore channels
  • STIM and Orai

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Published Papers (28 papers)

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Research

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Open AccessArticle
Type 2 Diabetes Alters Intracellular Ca2+ Handling in Native Endothelium of Excised Rat Aorta
Int. J. Mol. Sci. 2020, 21(1), 250; https://doi.org/10.3390/ijms21010250 - 30 Dec 2019
Abstract
An increase in intracellular Ca2+ concentration ([Ca2+]i) plays a key role in controlling endothelial functions; however, it is still unclear whether endothelial Ca2+ handling is altered by type 2 diabetes mellitus, which results in severe endothelial dysfunction. [...] Read more.
An increase in intracellular Ca2+ concentration ([Ca2+]i) plays a key role in controlling endothelial functions; however, it is still unclear whether endothelial Ca2+ handling is altered by type 2 diabetes mellitus, which results in severe endothelial dysfunction. Herein, we analyzed for the first time the Ca2+ response to the physiological autacoid ATP in native aortic endothelium of obese Zucker diabetic fatty (OZDF) rats and their lean controls, which are termed LZDF rats. By loading the endothelial monolayer with the Ca2+-sensitive fluorophore, Fura-2/AM, we found that the endothelial Ca2+ response to 20 µM and 300 µM ATP exhibited a higher plateau, a larger area under the curve and prolonged duration in OZDF rats. The “Ca2+ add-back” protocol revealed no difference in the inositol-1,4,5-trisphosphate-releasable endoplasmic reticulum (ER) Ca2+ pool, while store-operated Ca2+ entry was surprisingly down-regulated in OZDF aortae. Pharmacological manipulation disclosed that sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity was down-regulated by reactive oxygen species in native aortic endothelium of OZDF rats, thereby exaggerating the Ca2+ response to high agonist concentrations. These findings shed new light on the mechanisms by which type 2 diabetes mellitus may cause endothelial dysfunction by remodeling the intracellular Ca2+ toolkit. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessArticle
From Local to Global Modeling for Characterizing Calcium Dynamics and Their Effects on Electrical Activity and Exocytosis in Excitable Cells
Int. J. Mol. Sci. 2019, 20(23), 6057; https://doi.org/10.3390/ijms20236057 - 30 Nov 2019
Abstract
Electrical activity in neurons and other excitable cells is a result of complex interactions between the system of ion channels, involving both global coupling (e.g., via voltage or bulk cytosolic Ca2+ concentration) of the channels, and local coupling in ion channel complexes [...] Read more.
Electrical activity in neurons and other excitable cells is a result of complex interactions between the system of ion channels, involving both global coupling (e.g., via voltage or bulk cytosolic Ca2+ concentration) of the channels, and local coupling in ion channel complexes (e.g., via local Ca2+ concentration surrounding Ca2+ channels (CaVs), the so-called Ca2+ nanodomains). We recently devised a model of large-conductance BKCa potassium currents, and hence BKCa–CaV complexes controlled locally by CaVs via Ca2+ nanodomains. We showed how different CaV types and BKCa–CaV stoichiometries affect whole-cell electrical behavior. Ca2+ nanodomains are also important for triggering exocytosis of hormone-containing granules, and in this regard, we implemented a strategy to characterize the local interactions between granules and CaVs. In this study, we coupled electrical and exocytosis models respecting the local effects via Ca2+ nanodomains. By simulating scenarios with BKCa–CaV complexes with different stoichiometries in pituitary cells, we achieved two main electrophysiological responses (continuous spiking or bursting) and investigated their effects on the downstream exocytosis process. By varying the number and distance of CaVs coupled with the granules, we found that bursting promotes exocytosis with faster rates than spiking. However, by normalizing to Ca2+ influx, we found that bursting is only slightly more efficient than spiking when CaVs are far away from granules, whereas no difference in efficiency between bursting and spiking is observed with close granule-CaV coupling. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessCommunication
Changes in Calcium Homeostasis and Gene Expression Implicated in Epilepsy in Hippocampi of Mice Overexpressing ORAI1
Int. J. Mol. Sci. 2019, 20(22), 5539; https://doi.org/10.3390/ijms20225539 - 06 Nov 2019
Abstract
Previously, we showed that the overexpression of ORAI1 calcium channel in neurons of murine brain led to spontaneous occurrence of seizure-like events in aged animals of transgenic line FVB/NJ-Tg(ORAI1)Ibd (Nencki Institute of Experimental Biology). We aimed to identify the mechanism that is responsible [...] Read more.
Previously, we showed that the overexpression of ORAI1 calcium channel in neurons of murine brain led to spontaneous occurrence of seizure-like events in aged animals of transgenic line FVB/NJ-Tg(ORAI1)Ibd (Nencki Institute of Experimental Biology). We aimed to identify the mechanism that is responsible for this phenomenon. Using a modified Ca2+-addback assay in the CA1 region of acute hippocampal slices and FURA-2 acetomethyl ester (AM) Ca2+ indicator, we found that overexpression of ORAI1 in neurons led to altered Ca2+ response. Next, by RNA sequencing (RNAseq) we identified a set of genes, whose expression was changed in our transgenic animals. These data were validated using customized real-time PCR assays and digital droplet PCR (ddPCR) ddPCR. Using real-time PCR, up-regulation of hairy and enhancer of split-5 (Hes-5) gene and down-regulation of aristaless related homeobox (Arx), doublecortin-like kinase 1 (Dclk1), and cyclin-dependent kinase-like 5 (Cdkl5, also known as serine/threonine kinase 9 (Stk9)) genes were found. Digital droplet PCR (ddPCR) analysis revealed down-regulation of Arx. In humans, ARX, DCLK1, and CDLK5 were shown to be mutated in some rare epilepsy-associated disorders. We conclude that the occurrence of seizure-like events in aged mice overexpressing ORAI1 might be due to the down-regulation of Arx, and possibly of Cdkl5 and Dclk1 genes. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessArticle
ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca2+ Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model
Int. J. Mol. Sci. 2019, 20(20), 5151; https://doi.org/10.3390/ijms20205151 - 17 Oct 2019
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca2+-ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessArticle
ATP-Evoked Intracellular Ca2+ Responses in M-CSF Differentiated Human Monocyte-Derived Macrophage are Mediated by P2X4 and P2Y11 Receptor Activation
Int. J. Mol. Sci. 2019, 20(20), 5113; https://doi.org/10.3390/ijms20205113 - 15 Oct 2019
Abstract
Tissues differentially secrete multiple colony stimulating factors under conditions of homeostasis and inflammation, orientating recruited circulating monocytes to differentiate to macrophage with differing functional phenotypes. Here, we investigated ATP-evoked intracellular Ca2+ responses in human macrophage differentiated with macrophage colony-stimulating factor (M-CSF). Extracellular [...] Read more.
Tissues differentially secrete multiple colony stimulating factors under conditions of homeostasis and inflammation, orientating recruited circulating monocytes to differentiate to macrophage with differing functional phenotypes. Here, we investigated ATP-evoked intracellular Ca2+ responses in human macrophage differentiated with macrophage colony-stimulating factor (M-CSF). Extracellular ATP evoked (EC50 13.3 ± 1.4 μM) robust biphasic intracellular Ca2+ responses that showed a dependency on both metabotropic (P2Y) and ionotropic (P2X) receptors. qRT-PCR and immunocytochemistry revealed the expression of P2Y1, P2Y2, P2Y6, P2Y11, P2Y13, P2X1, P2X4, P2X5, and P2X7. Pharmacological analysis revealed contribution of only P2X4 and P2Y11 to the Ca2+ response evoked by maximal ATP concentrations (100 µM). This study reveals the contribution of P2X4 and P2Y11 receptor activation to ATP-evoked intracellular Ca2+ responses, and makes comparison with macrophage differentiated using granulocyte colony-stimulating factor (GM-CSF). Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessArticle
Angiotensin-II Drives Human Satellite Cells Toward Hypertrophy and Myofibroblast Trans-Differentiation by Two Independent Pathways
Int. J. Mol. Sci. 2019, 20(19), 4912; https://doi.org/10.3390/ijms20194912 - 03 Oct 2019
Abstract
Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector [...] Read more.
Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessArticle
Bisphenol A Activates Calcium Influx in Immortalized GnRH Neurons
Int. J. Mol. Sci. 2019, 20(9), 2160; https://doi.org/10.3390/ijms20092160 - 01 May 2019
Abstract
Bisphenol A (BPA) is one of the most widely used chemicals worldwide, e.g., as a component of plastic containers for food and water. It is considered to exert an estrogenic effect, by mimicking estradiol (E2) action. Because of this widespread presence, it has [...] Read more.
Bisphenol A (BPA) is one of the most widely used chemicals worldwide, e.g., as a component of plastic containers for food and water. It is considered to exert an estrogenic effect, by mimicking estradiol (E2) action. Because of this widespread presence, it has attracted the interest and concern of researchers and regulators. Despite the vast amount of related literature, the potential adverse effects of environmentally significant doses of BPA are still object of controversy, and the mechanisms by which it can perturb endocrine functions, and particularly the neuroendocrine axis, are not adequately understood. One of the ways by which endocrine disruptors (EDCs) can exert their effects is the perturbation of calcium signaling mechanisms. In this study, we addressed the issue of the impact of BPA on the neuroendocrine system with an in vitro approach, using a consolidated model of immortalized Gonadotropin-Releasing Hormone (GnRH) expressing neurons, the GT1–7 cell line, focusing on the calcium signals activated by the endocrine disruptor. The investigation was limited to biologically relevant doses (nM–µM range). We found that BPA induced moderate increases in intracellular calcium concentration, comparable with those induced by nanomolar doses of E2, without affecting cell survival and with only a minor effect on proliferation. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessArticle
Calcium Activity Dynamics Correlate with Neuronal Phenotype at a Single Cell Level and in a Threshold-Dependent Manner
Int. J. Mol. Sci. 2019, 20(8), 1880; https://doi.org/10.3390/ijms20081880 - 16 Apr 2019
Abstract
Calcium is a ubiquitous signaling molecule that plays a vital role in many physiological processes. Recent work has shown that calcium activity is especially critical in vertebrate neural development. Here, we investigated if calcium activity and neuronal phenotype are correlated only on a [...] Read more.
Calcium is a ubiquitous signaling molecule that plays a vital role in many physiological processes. Recent work has shown that calcium activity is especially critical in vertebrate neural development. Here, we investigated if calcium activity and neuronal phenotype are correlated only on a population level or on the level of single cells. Using Xenopus primary cell culture in which individual cells can be unambiguously identified and associated with a molecular phenotype, we correlated calcium activity with neuronal phenotype on the single-cell level. This analysis revealed that, at the neural plate stage, a high frequency of low-amplitude spiking activity correlates with an excitatory, glutamatergic phenotype, while high-amplitude spiking activity correlates with an inhibitory, GABAergic phenotype. Surprisingly, we also found that high-frequency, low-amplitude spiking activity correlates with neural progenitor cells and that differentiating cells exhibit higher spike amplitude. Additional methods of analysis suggested that differentiating marker tubb2b-expressing cells exhibit relatively persistent and predictable calcium activity compared to the irregular activity of neural progenitor cells. Our study highlights the value of using a range of thresholds for analyzing calcium activity data and underscores the importance of employing multiple methods to characterize the often irregular, complex patterns of calcium activity during early neural development. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessArticle
Empagliflozin Attenuates Myocardial Sodium and Calcium Dysregulation and Reverses Cardiac Remodeling in Streptozotocin-Induced Diabetic Rats
Int. J. Mol. Sci. 2019, 20(7), 1680; https://doi.org/10.3390/ijms20071680 - 04 Apr 2019
Cited by 2
Abstract
Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca2+) and sodium (Na+) regulation. Clinical studies have shown that empagliflozin (Jardiance™) has cardiovascular benefits, however the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin [...] Read more.
Diabetes mellitus (DM) has significant effects on cardiac calcium (Ca2+) and sodium (Na+) regulation. Clinical studies have shown that empagliflozin (Jardiance™) has cardiovascular benefits, however the mechanisms have not been fully elucidated. This study aimed to investigate whether empagliflozin modulates cardiac electrical activity as well as Ca2+/Na+ homeostasis in DM cardiomyopathy. Electrocardiography, echocardiography, whole-cell patch-clamp, confocal microscopic examinations, and Western blot, were performed in the ventricular myocytes of control and streptozotocin-induced DM rats, with or without empagliflozin (10 mg/kg for 4 weeks). The results showed that the control and empagliflozin-treated DM rats had smaller left ventricular end-diastolic diameters and shorter QT intervals than the DM rats. In addition, the prolonged action potential duration in the DM rats was attenuated in the empagliflozin-treated DM rats. Moreover, the DM rats had smaller sarcoplasmic reticular Ca2+ contents, intracellular Ca2+ transients, L-type Ca2+, reverse mode Na+-Ca2+exchanger currents, lower protein expressions of sarcoplasmic reticulum ATPase, ryanodine receptor 2 (RyR2), but higher protein expressions of phosphorylated RyR2 at serine 2808 than the control and empagliflozin-treated DM rats. The incidence and frequency of Ca2+ sparks, cytosolic and mitochondrial reactive oxygen species, and late Na+ current and Na+/hydrogen-exchanger currents were greater in the DM rats than in the control and empagliflozin-treated DM rats. Empagliflozin significantly changed Ca2+ regulation, late Na+ and Na+/hydrogen-exchanger currents and electrophysiological characteristics in DM cardiomyopathy, which may contribute to its cardioprotective benefits in DM patients. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Review

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Open AccessReview
Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)
Int. J. Mol. Sci. 2020, 21(1), 216; https://doi.org/10.3390/ijms21010216 - 27 Dec 2019
Abstract
Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular [...] Read more.
Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells. Ca2+ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca2+ channels, Ca2+-dependent kinases and phosphatases, and Ca2+-binding proteins to tightly maintain Ca2+ homeostasis and regulate physiological Ca2+-dependent processes. Abnormal Ca2+ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca2+ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessReview
TLQP-21, A VGF-Derived Peptide Endowed of Endocrine and Extraendocrine Properties: Focus on In Vitro Calcium Signaling
Int. J. Mol. Sci. 2020, 21(1), 130; https://doi.org/10.3390/ijms21010130 - 24 Dec 2019
Abstract
VGF gene encodes for a neuropeptide precursor of 68 kDa composed by 615 (human) and 617 (rat, mice) residues, expressed prevalently in the central nervous system (CNS), but also in the peripheral nervous system (PNS) and in various endocrine cells. This precursor undergoes [...] Read more.
VGF gene encodes for a neuropeptide precursor of 68 kDa composed by 615 (human) and 617 (rat, mice) residues, expressed prevalently in the central nervous system (CNS), but also in the peripheral nervous system (PNS) and in various endocrine cells. This precursor undergoes proteolytic cleavage, generating a family of peptides different in length and biological activity. Among them, TLQP-21, a peptide of 21 amino acids, has been widely investigated for its relevant endocrine and extraendocrine activities. The complement complement C3a receptor-1 (C3aR1) has been suggested as the TLQP-21 receptor and, in different cell lines, its activation by TLQP-21 induces an increase of intracellular Ca2+. This effect relies both on Ca2+ release from the endoplasmic reticulum (ER) and extracellular Ca2+ entry. The latter depends on stromal interaction molecules (STIM)-Orai1 interaction or transient receptor potential channel (TRPC) involvement. After Ca2+ entry, the activation of outward K+-Ca2+-dependent currents, mainly the KCa3.1 currents, provides a membrane polarizing influence which offset the depolarizing action of Ca2+ elevation and indirectly maintains the driving force for optimal Ca2+ increase in the cytosol. In this review, we address the main endocrine and extraendocrine actions displayed by TLQP-21, highlighting recent findings on its mechanism of action and its potential in different pathological conditions. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessReview
Partners in Crime: Towards New Ways of Targeting Calcium Channels
Int. J. Mol. Sci. 2019, 20(24), 6344; https://doi.org/10.3390/ijms20246344 - 16 Dec 2019
Abstract
The characterization of calcium channel interactome in the last decades opened a new way of perceiving ion channel function and regulation. Partner proteins of ion channels can now be considered as major components of the calcium homeostatic mechanisms, while the reinforcement or disruption [...] Read more.
The characterization of calcium channel interactome in the last decades opened a new way of perceiving ion channel function and regulation. Partner proteins of ion channels can now be considered as major components of the calcium homeostatic mechanisms, while the reinforcement or disruption of their interaction with the channel units now represents an attractive target in research and therapeutics. In this review we will focus on the targeting of calcium channel partner proteins in order to act on the channel activity, and on its consequences for cell and organism physiology. Given the recent advances in the partner proteins’ identification, characterization, as well as in the resolution of their interaction domain structures, we will develop the latest findings on the interacting proteins of the following channels: voltage-dependent calcium channels, transient receptor potential and ORAI channels, and inositol 1,4,5-trisphosphate receptor. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessReview
Calcium Signaling in ß-cell Physiology and Pathology: A Revisit
Int. J. Mol. Sci. 2019, 20(24), 6110; https://doi.org/10.3390/ijms20246110 - 04 Dec 2019
Abstract
Pancreatic beta (β) cell dysfunction results in compromised insulin release and, thus, failed regulation of blood glucose levels. This forms the backbone of the development of diabetes mellitus (DM), a disease that affects a significant portion of the global adult population. Physiological calcium [...] Read more.
Pancreatic beta (β) cell dysfunction results in compromised insulin release and, thus, failed regulation of blood glucose levels. This forms the backbone of the development of diabetes mellitus (DM), a disease that affects a significant portion of the global adult population. Physiological calcium (Ca2+) signaling has been found to be vital for the proper insulin-releasing function of β-cells. Calcium dysregulation events can have a dramatic effect on the proper functioning of the pancreatic β-cells. The current review discusses the role of calcium signaling in health and disease in pancreatic β-cells and provides an in-depth look into the potential role of alterations in β-cell Ca2+ homeostasis and signaling in the development of diabetes and highlights recent work that introduced the current theories on the connection between calcium and the onset of diabetes. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessReview
The Interplay between Ca2+ Signaling Pathways and Neurodegeneration
Int. J. Mol. Sci. 2019, 20(23), 6004; https://doi.org/10.3390/ijms20236004 - 28 Nov 2019
Abstract
Calcium (Ca2+) homeostasis is essential for cell maintenance since this ion participates in many physiological processes. For example, the spatial and temporal organization of Ca2+ signaling in the central nervous system is fundamental for neurotransmission, where local changes in cytosolic [...] Read more.
Calcium (Ca2+) homeostasis is essential for cell maintenance since this ion participates in many physiological processes. For example, the spatial and temporal organization of Ca2+ signaling in the central nervous system is fundamental for neurotransmission, where local changes in cytosolic Ca2+ concentration are needed to transmit information from neuron to neuron, between neurons and glia, and even regulating local blood flow according to the required activity. However, under pathological conditions, Ca2+ homeostasis is altered, with increased cytoplasmic Ca2+ concentrations leading to the activation of proteases, lipases, and nucleases. This review aimed to highlight the role of Ca2+ signaling in neurodegenerative disease-related apoptosis, where the regulation of intracellular Ca2+ homeostasis depends on coordinated interactions between the endoplasmic reticulum, mitochondria, and lysosomes, as well as specific transport mechanisms. In neurodegenerative diseases, alterations-increased oxidative stress, energy metabolism alterations, and protein aggregation have been identified. The aggregation of α-synuclein, β-amyloid peptide (Aβ), and huntingtin all adversely affect Ca2+ homeostasis. Due to the mounting evidence for the relevance of Ca2+ signaling in neuroprotection, we would focus on the expression and function of Ca2+ signaling-related proteins, in terms of the effects on autophagy regulation and the onset and progression of neurodegenerative diseases. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessReview
G Protein-Coupled Receptors (GPCRs)-Mediated Calcium Signaling in Ovarian Cancer: Focus on GPCRs activated by Neurotransmitters and Inflammation-Associated Molecules
Int. J. Mol. Sci. 2019, 20(22), 5568; https://doi.org/10.3390/ijms20225568 - 07 Nov 2019
Abstract
G-coupled protein receptors (GCPR) involve several signaling pathways, some of them being coupled with intracellular calcium (Ca2+) mobilization. GPCRs were involved in migration, invasion and metastasis of different types of cancers, including ovarian cancer. Many studies have discussed the essential contribution [...] Read more.
G-coupled protein receptors (GCPR) involve several signaling pathways, some of them being coupled with intracellular calcium (Ca2+) mobilization. GPCRs were involved in migration, invasion and metastasis of different types of cancers, including ovarian cancer. Many studies have discussed the essential contribution of GPCRs activated by steroid hormones in ovarian cancer. However, ovarian cancer is also associated with altered signals coming from the nervous system, the immune system or the inflammatory environment, in which GPCRs are ‘sensing’ these molecular signals. Many studies have been oriented so far on ovarian cell lines (most of them being of human cell lines), and only few studies based on animal models or clinical studies have been devoted to the expression changes or functional role of GPCRs in ovarian cancer. In this paper, we review the alterations of GPCRs activated by neurotransmitters (muscarinic receptors, serotonin receptors, dopamine receptors, adrenoceptors) or inflammation-associated molecules (bradykinin receptors, histamine receptors, chemokine receptors) in ovarian cancer and we discuss their potential as histological biomarkers. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Open AccessReview
Renal Ca2+ and Water Handling in Response to Calcium Sensing Receptor Signaling: Physiopathological Aspects and Role of CaSR-Regulated microRNAs
Int. J. Mol. Sci. 2019, 20(21), 5341; https://doi.org/10.3390/ijms20215341 - 27 Oct 2019
Cited by 1
Abstract
Calcium (Ca2+) is a universal and vital intracellular messenger involved in a diverse range of cellular and biological processes. Changes in the concentration of extracellular Ca2+ can disrupt the normal cellular activities and the physiological function of these systems. The [...] Read more.
Calcium (Ca2+) is a universal and vital intracellular messenger involved in a diverse range of cellular and biological processes. Changes in the concentration of extracellular Ca2+ can disrupt the normal cellular activities and the physiological function of these systems. The calcium sensing receptor (CaSR) is a unique G protein-coupled receptor (GPCR) activated by extracellular Ca2+ and by other physiological cations, aminoacids, and polyamines. CaSR is the main controller of the extracellular Ca2+ homeostatic system by regulating parathyroid hormone (PTH) secretion and, in turn, Ca2+ absorption and resorption. Recent advances highlight novel signaling pathways activated by CaSR signaling involving the regulation of microRNAs (miRNAs). miRNAs are naturally-occurring small non-coding RNAs that regulate post-transcriptional gene expression and are involved in several diseases. We previously described that high luminal Ca2+ in the renal collecting duct attenuates short-term vasopressin-induced aquaporin-2 (AQP2) trafficking through CaSR activation. Moreover, we demonstrated that CaSR signaling reduces AQP2 abundance via AQP2-targeting miRNA-137. This review summarizes the recent data related to CaSR-regulated miRNAs signaling pathways in the kidney. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy
Int. J. Mol. Sci. 2019, 20(21), 5304; https://doi.org/10.3390/ijms20215304 - 24 Oct 2019
Abstract
Cardiac arrhythmias constitute a major health problem with a huge impact on mortality rates and health care costs. Despite ongoing research efforts, the understanding of the molecular mechanisms and processes responsible for arrhythmogenesis remains incomplete. Given the crucial role of Ca2+-handling [...] Read more.
Cardiac arrhythmias constitute a major health problem with a huge impact on mortality rates and health care costs. Despite ongoing research efforts, the understanding of the molecular mechanisms and processes responsible for arrhythmogenesis remains incomplete. Given the crucial role of Ca2+-handling in action potential generation and cardiac contraction, Ca2+ channels and Ca2+ handling proteins represent promising targets for suppression of ventricular arrhythmias. Accordingly, we report the different roles of Ca2+-handling in the development of congenital as well as acquired ventricular arrhythmia syndromes. We highlight the therapeutic potential of gene therapy as a novel and innovative approach for future arrhythmia therapy. Furthermore, we discuss various promising cellular and mitochondrial targets for therapeutic gene transfer currently under investigation. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Mitochondrial Calcium Uniporter Structure and Function in Different Types of Muscle Tissues in Health and Disease
Int. J. Mol. Sci. 2019, 20(19), 4823; https://doi.org/10.3390/ijms20194823 - 28 Sep 2019
Cited by 1
Abstract
Calcium ions (Ca2+) influx to mitochondrial matrix is crucial for the life of a cell. Mitochondrial calcium uniporter (mtCU) is a protein complex which consists of the pore-forming subunit (MCU) and several regulatory subunits. MtCU is the main contributor to inward [...] Read more.
Calcium ions (Ca2+) influx to mitochondrial matrix is crucial for the life of a cell. Mitochondrial calcium uniporter (mtCU) is a protein complex which consists of the pore-forming subunit (MCU) and several regulatory subunits. MtCU is the main contributor to inward Ca2+ currents through the inner mitochondrial membrane. Extensive investigations of mtCU involvement into normal and pathological molecular pathways started from the moment of discovery of its molecular components. A crucial role of mtCU in the control of these pathways is now recognized in both health and disease. In particular, impairments of mtCU function have been demonstrated for cardiovascular and skeletal muscle-associated pathologies. This review summarizes the current state of knowledge on mtCU structure, regulation, and function in different types of muscle tissues in health and disease. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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The Link of the Prion Protein with Ca2+ Metabolism and ROS Production, and the Possible Implication in Aβ Toxicity
Int. J. Mol. Sci. 2019, 20(18), 4640; https://doi.org/10.3390/ijms20184640 - 19 Sep 2019
Abstract
The cellular prion protein (PrPC) is an ubiquitous cell surface protein mostly expressed in neurons, where it localizes to both pre- and post-synaptic membranes. PrPC aberrant conformers are the major components of mammalian prions, the infectious agents responsible for incurable [...] Read more.
The cellular prion protein (PrPC) is an ubiquitous cell surface protein mostly expressed in neurons, where it localizes to both pre- and post-synaptic membranes. PrPC aberrant conformers are the major components of mammalian prions, the infectious agents responsible for incurable neurodegenerative disorders. PrPC was also proposed to bind aggregated misfolded proteins/peptides, and to mediate their neurotoxic signal. In spite of long-lasting research, a general consensus on the precise pathophysiologic mechanisms of PrPC has not yet been reached. Here we review our recent data, obtained by comparing primary neurons from PrP-expressing and PrP-knockout mice, indicating a central role of PrPC in synaptic transmission and Ca2+ homeostasis. Indeed, by controlling gene expression and signaling cascades, PrPC is able to optimize glutamate secretion and regulate Ca2+ entry via store-operated channels and ionotropic glutamate receptors, thereby protecting neurons from threatening Ca2+ overloads and excitotoxicity. We will also illustrate and discuss past and unpublished results demonstrating that Aβ oligomers perturb Ca2+ homeostasis and cause abnormal mitochondrial accumulation of reactive oxygen species by possibly affecting the PrP-dependent downregulation of Fyn kinase activity. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Calcium Mobilization in Endothelial Cell Functions
Int. J. Mol. Sci. 2019, 20(18), 4525; https://doi.org/10.3390/ijms20184525 - 12 Sep 2019
Abstract
Endothelial cells (ECs) constitute the innermost layer that lines all blood vessels from the larger arteries and veins to the smallest capillaries, including the lymphatic vessels. Despite the histological classification of endothelium of a simple epithelium and its homogeneous morphological appearance throughout the [...] Read more.
Endothelial cells (ECs) constitute the innermost layer that lines all blood vessels from the larger arteries and veins to the smallest capillaries, including the lymphatic vessels. Despite the histological classification of endothelium of a simple epithelium and its homogeneous morphological appearance throughout the vascular system, ECs, instead, are extremely heterogeneous both structurally and functionally. The different arrangement of cell junctions between ECs and the local organization of the basal membrane generate different type of endothelium with different permeability features and functions. Continuous, fenestrated and discontinuous endothelia are distributed based on the specific function carried out by the organs. It is thought that a large number ECs functions and their responses to extracellular cues depend on changes in intracellular concentrations of calcium ion ([Ca2+]i). The extremely complex calcium machinery includes plasma membrane bound channels as well as intracellular receptors distributed in distinct cytosolic compartments that act jointly to maintain a physiological [Ca2+]i, which is crucial for triggering many cellular mechanisms. Here, we first survey the overall notions related to intracellular Ca2+ mobilization and later highlight the involvement of this second messenger in crucial ECs functions with the aim at stimulating further investigation that link Ca2+ mobilization to ECs in health and disease. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
Open AccessReview
CaMKII Activity in the Inflammatory Response of Cardiac Diseases
Int. J. Mol. Sci. 2019, 20(18), 4374; https://doi.org/10.3390/ijms20184374 - 06 Sep 2019
Cited by 1
Abstract
Inflammation is a physiological process by which the body responds to external insults and stress conditions, and it is characterized by the production of pro-inflammatory mediators such as cytokines. The acute inflammatory response is solved by removing the threat. Conversely, a chronic inflammatory [...] Read more.
Inflammation is a physiological process by which the body responds to external insults and stress conditions, and it is characterized by the production of pro-inflammatory mediators such as cytokines. The acute inflammatory response is solved by removing the threat. Conversely, a chronic inflammatory state is established due to a prolonged inflammatory response and may lead to tissue damage. Based on the evidence of a reciprocal regulation between inflammation process and calcium unbalance, here we described the involvement of a calcium sensor in cardiac diseases with inflammatory drift. Indeed, the Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated in several diseases with an inflammatory component, such as myocardial infarction, ischemia/reperfusion injury, pressure overload/hypertrophy, and arrhythmic syndromes, in which it actively regulates pro-inflammatory signaling, among which includes nuclear factor kappa-B (NF-κB), thus contributing to pathological cardiac remodeling. Thus, CaMKII may represent a key target to modulate the severity of the inflammatory-driven degeneration. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Growth Hormone Secretagogues and the Regulation of Calcium Signaling in Muscle
Int. J. Mol. Sci. 2019, 20(18), 4361; https://doi.org/10.3390/ijms20184361 - 05 Sep 2019
Abstract
Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a [...] Read more.
Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia–reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Calcium as a Key Player in Arrhythmogenic Cardiomyopathy: Adhesion Disorder or Intracellular Alteration?
Int. J. Mol. Sci. 2019, 20(16), 3986; https://doi.org/10.3390/ijms20163986 - 16 Aug 2019
Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic [...] Read more.
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic signaling pathways, and induce fibro-adipose replacement. Here, we discuss the hypothesis that the ACM causative mechanism involves a defect in the expression and/or activity of the cardiac Ca2+ handling machinery, focusing on the available data supporting this hypothesis. The Ca2+ toolkit is heavily remodeled in cardiomyocytes derived from a mouse model of ACM defective of the desmosomal protein plakophilin-2. Furthermore, ACM-related mutations were found in genes encoding for proteins involved in excitation‒contraction coupling, e.g., type 2 ryanodine receptor and phospholamban. As a consequence, the sarcoplasmic reticulum becomes more eager to release Ca2+, thereby inducing delayed afterdepolarizations and impairing cardiac contractility. These data are supported by preliminary observations from patient induced pluripotent stem-cell-derived cardiomyocytes. Assessing the involvement of Ca2+ signaling in the pathogenesis of ACM could be beneficial in the treatment of this life-threatening disease. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Endothelial Ca2+ Signaling, Angiogenesis and Vasculogenesis: Just What It Takes to Make a Blood Vessel
Int. J. Mol. Sci. 2019, 20(16), 3962; https://doi.org/10.3390/ijms20163962 - 14 Aug 2019
Cited by 3
Abstract
It has long been known that endothelial Ca2+ signals drive angiogenesis by recruiting multiple Ca2+-sensitive decoders in response to pro-angiogenic cues, such as vascular endothelial growth factor, basic fibroblast growth factor, stromal derived factor-1α and angiopoietins. Recently, it was shown [...] Read more.
It has long been known that endothelial Ca2+ signals drive angiogenesis by recruiting multiple Ca2+-sensitive decoders in response to pro-angiogenic cues, such as vascular endothelial growth factor, basic fibroblast growth factor, stromal derived factor-1α and angiopoietins. Recently, it was shown that intracellular Ca2+ signaling also drives vasculogenesis by stimulation proliferation, tube formation and neovessel formation in endothelial progenitor cells. Herein, we survey how growth factors, chemokines and angiogenic modulators use endothelial Ca2+ signaling to regulate angiogenesis and vasculogenesis. The endothelial Ca2+ response to pro-angiogenic cues may adopt different waveforms, ranging from Ca2+ transients or biphasic Ca2+ signals to repetitive Ca2+ oscillations, and is mainly driven by endogenous Ca2+ release through inositol-1,4,5-trisphosphate receptors and by store-operated Ca2+ entry through Orai1 channels. Lysosomal Ca2+ release through nicotinic acid adenine dinucleotide phosphate-gated two-pore channels is, however, emerging as a crucial pro-angiogenic pathway, which sustains intracellular Ca2+ mobilization. Understanding how endothelial Ca2+ signaling regulates angiogenesis and vasculogenesis could shed light on alternative strategies to induce therapeutic angiogenesis or interfere with the aberrant vascularization featuring cancer and intraocular disorders. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Endothelium-Dependent Hyperpolarization (EDH) in Diabetes: Mechanistic Insights and Therapeutic Implications
Int. J. Mol. Sci. 2019, 20(15), 3737; https://doi.org/10.3390/ijms20153737 - 31 Jul 2019
Abstract
Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and [...] Read more.
Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and the hyperpolarization of vascular smooth muscle cells mediated by the endothelium plays a central role in agonist-mediated and flow-mediated vasodilation in resistance-size vessels. Although the mechanisms underlying diabetic vascular complications are multifactorial and complex, impairment of endothelium-dependent hyperpolarization (EDH) of vascular smooth muscle cells would contribute at least partly to the initiation and progression of microvascular complications of diabetes. In this review, we present the current knowledge about the pathophysiology and underlying mechanisms of impaired EDH in diabetes in animals and humans. We also discuss potential therapeutic approaches aimed at the prevention and restoration of EDH in diabetes. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection
Int. J. Mol. Sci. 2019, 20(12), 3017; https://doi.org/10.3390/ijms20123017 - 20 Jun 2019
Cited by 1
Abstract
Calcium (Ca2+) signaling and the modulation of intracellular calcium ([Ca2+]i) levels play critical roles in several key processes that regulate cellular survival, growth, differentiation, metabolism, and death in normal cells. On the other hand, aberrant Ca2+ [...] Read more.
Calcium (Ca2+) signaling and the modulation of intracellular calcium ([Ca2+]i) levels play critical roles in several key processes that regulate cellular survival, growth, differentiation, metabolism, and death in normal cells. On the other hand, aberrant Ca2+-signaling and loss of [Ca2+]i homeostasis contributes to tumor initiation proliferation, angiogenesis, and other key processes that support tumor progression in several different cancers. Currently, chemically and functionally distinct drugs are used as chemotherapeutic agents in the treatment and management of cancer among which certain anti-cancer drugs reportedly suppress pro-survival signals and activate pro-apoptotic signaling through modulation of Ca2+-signaling-dependent mechanisms. Most importantly, the modulation of [Ca2+]i levels via the endoplasmic reticulum-mitochondrial axis and corresponding action of channels and pumps within the plasma membrane play an important role in the survival and death of cancer cells. The endoplasmic reticulum-mitochondrial axis is of prime importance when considering Ca2+-signaling-dependent anti-cancer drug targets. This review discusses how calcium signaling is targeted by anti-cancer drugs and highlights the role of calcium signaling in epigenetic modification and the Warburg effect in tumorigenesis. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Functional Interaction among KCa and TRP Channels for Cardiovascular Physiology: Modern Perspectives on Aging and Chronic Disease
Int. J. Mol. Sci. 2019, 20(6), 1380; https://doi.org/10.3390/ijms20061380 - 19 Mar 2019
Cited by 5
Abstract
Effective delivery of oxygen and essential nutrients to vital organs and tissues throughout the body requires adequate blood flow supplied through resistance vessels. The intimate relationship between intracellular calcium ([Ca2+]i) and regulation of membrane potential (Vm) is [...] Read more.
Effective delivery of oxygen and essential nutrients to vital organs and tissues throughout the body requires adequate blood flow supplied through resistance vessels. The intimate relationship between intracellular calcium ([Ca2+]i) and regulation of membrane potential (Vm) is indispensable for maintaining blood flow regulation. In particular, Ca2+-activated K+ (KCa) channels were ascertained as transducers of elevated [Ca2+]i signals into hyperpolarization of Vm as a pathway for decreasing vascular resistance, thereby enhancing blood flow. Recent evidence also supports the reverse role for KCa channels, in which they facilitate Ca2+ influx into the cell interior through open non-selective cation (e.g., transient receptor potential; TRP) channels in accord with robust electrical (hyperpolarization) and concentration (~20,000-fold) transmembrane gradients for Ca2+. Such an arrangement supports a feed-forward activation of Vm hyperpolarization while potentially boosting production of nitric oxide. Furthermore, in vascular types expressing TRP channels but deficient in functional KCa channels (e.g., collecting lymphatic endothelium), there are profound alterations such as downstream depolarizing ionic fluxes and the absence of dynamic hyperpolarizing events. Altogether, this review is a refined set of evidence-based perspectives focused on the role of the endothelial KCa and TRP channels throughout multiple experimental animal models and vascular types. We discuss the diverse interactions among KCa and TRP channels to integrate Ca2+, oxidative, and electrical signaling in the context of cardiovascular physiology and pathology. Building from a foundation of cellular biophysical data throughout a wide and diverse compilation of significant discoveries, a translational narrative is provided for readers toward the treatment and prevention of chronic, age-related cardiovascular disease. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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Molecular Mechanisms of Leucine Zipper EF-Hand Containing Transmembrane Protein-1 Function in Health and Disease
Int. J. Mol. Sci. 2019, 20(2), 286; https://doi.org/10.3390/ijms20020286 - 12 Jan 2019
Cited by 3
Abstract
Mitochondrial calcium (Ca2+) uptake shapes cytosolic Ca2+ signals involved in countless cellular processes and more directly regulates numerous mitochondrial functions including ATP production, autophagy and apoptosis. Given the intimate link to both life and death processes, it is imperative that [...] Read more.
Mitochondrial calcium (Ca2+) uptake shapes cytosolic Ca2+ signals involved in countless cellular processes and more directly regulates numerous mitochondrial functions including ATP production, autophagy and apoptosis. Given the intimate link to both life and death processes, it is imperative that mitochondria tightly regulate intramitochondrial Ca2+ levels with a high degree of precision. Among the Ca2+ handling tools of mitochondria, the leucine zipper EF-hand containing transmembrane protein-1 (LETM1) is a transporter protein localized to the inner mitochondrial membrane shown to constitute a Ca2+/H+ exchanger activity. The significance of LETM1 to mitochondrial Ca2+ regulation is evident from Wolf-Hirschhorn syndrome patients that harbor a haplodeficiency in LETM1 expression, leading to dysfunctional mitochondrial Ca2+ handling and from numerous types of cancer cells that show an upregulation of LETM1 expression. Despite the significance of LETM1 to cell physiology and pathophysiology, the molecular mechanisms of LETM1 function remain poorly defined. In this review, we aim to provide an overview of the current understanding of LETM1 structure and function and pinpoint the knowledge gaps that need to be filled in order to unravel the underlying mechanistic basis for LETM1 function. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
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