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Calcium Handling 2.0
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Calcium Handling 2.0

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 14713

Special Issue Editor

Dr. Demetrios A. Arvanitis

E-Mail Website
Guest Editor
Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece
Interests: cell biology; physiology; genetics; calcium, cardiomyocytes; neurons
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Calcium ion (Ca2+) handling is the central coordinator of excitable cell functions. For neuronal, skeletal, cardiac, or smooth muscle, and pancreatic beta cells, transient elevation of intracellular Ca2+ triggers molecular machines and produces key cellular responses, such as contraction and secretion. This is mediated through the maintenance of the resting cytosolic Ca2+ concentration, four orders of magnitude lower than the extracellular space and three orders of magnitude lower than the endoplasmic reticulum or the mitochondria. Upon excitation, these Ca2+ stores release Ca2+ to the cytosol through ion channels, while during relaxation, ATPase pumps reuptake cytosolic Ca2+ to its stores. These channels and pumps are under the control of accessory proteins that modify their function upon extracellular or intracellular signaling. Genetic variations, protein modifications, and expression changes of the molecules involved have been associated with human diseases. Targeting druggable Ca2+ handling proteins may serve as therapy for neuronal, skeletal muscle, and cardiac or endocrinal diseases. This issue of IJMS (“Calcium Handling 2.0”) presents novel research and reviews in the field of Ca2+ handling proteins’ molecular interplay and regulation in cell physiology and pathophysiology.

Dr. Demetrios A. Arvanitis
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • Ca2+
  • endoplasmic reticulum
  • mitochondria
  • neurons
  • skeletal muscle
  • cardiac muscle
  • smooth muscle
  • pancreatic beta cells
  • contractility
  • secretion

Related Special Issue

Published Papers (7 papers)

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Research

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19 pages, 3771 KiB  
Article
Ca2+ Dependent Formation/Collapse of Cylindrical Ca2+-ATPase Crystals in Scallop Sarcoplasmic Reticulum (SR) Vesicles: A Possible Dynamic Role of SR in Regulation of Muscle Contraction
by Jun Nakamura, Yuusuke Maruyama, Genichi Tajima, Satoshi Hayakawa, Makiko Suwa and Chikara Sato
Int. J. Mol. Sci. 2023, 24(8), 7080; https://doi.org/10.3390/ijms24087080 - 11 Apr 2023
Viewed by 1371
Abstract
[Ca2+]-dependent crystallization of the Ca2+-ATPase molecules in sarcoplasmic reticulum (SR) vesicles isolated from scallop striated muscle elongated the vesicles in the absence of ATP, and ATP stabilized the crystals. Here, to determine the [Ca2+]-dependence of vesicle elongation [...] Read more.
[Ca2+]-dependent crystallization of the Ca2+-ATPase molecules in sarcoplasmic reticulum (SR) vesicles isolated from scallop striated muscle elongated the vesicles in the absence of ATP, and ATP stabilized the crystals. Here, to determine the [Ca2+]-dependence of vesicle elongation in the presence of ATP, SR vesicles in various [Ca2+] environments were imaged using negative stain electron microscopy. The images obtained revealed the following phenomena. (i) Crystal-containing elongated vesicles appeared at ≤1.4 µM Ca2+ and almost disappeared at ≥18 µM Ca2+, where ATPase activity reaches its maximum. (ii) At ≥18 µM Ca2+, almost all SR vesicles were in the round form and covered by tightly clustered ATPase crystal patches. (iii) Round vesicles dried on electron microscopy grids occasionally had cracks, probably because surface tension crushed the solid three-dimensional spheres. (iv) [Ca2+]-dependent ATPase crystallization was rapid (<1 min) and reversible. These data prompt the hypothesis that SR vesicles autonomously elongate or contract with the help of a calcium-sensitive ATPase network/endoskeleton and that ATPase crystallization may modulate physical properties of the SR architecture, including the ryanodine receptors that control muscle contraction. Full article
(This article belongs to the Special Issue Calcium Handling 2.0)
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16 pages, 2984 KiB  
Article
Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue
by Limor Arbel Ganon, Moran Davoodi, Alexandra Alexandrovich and Yael Yaniv
Int. J. Mol. Sci. 2023, 24(6), 5786; https://doi.org/10.3390/ijms24065786 - 17 Mar 2023
Viewed by 1432
Abstract
Bradycardia is initiated by the sinoatrial node (SAN), which is regulated by a coupled-clock system. Due to the clock coupling, reduction in the ‘funny’ current (If), which affects SAN automaticity, can be compensated, thus preventing severe bradycardia. We hypothesize that this [...] Read more.
Bradycardia is initiated by the sinoatrial node (SAN), which is regulated by a coupled-clock system. Due to the clock coupling, reduction in the ‘funny’ current (If), which affects SAN automaticity, can be compensated, thus preventing severe bradycardia. We hypothesize that this fail-safe system is an inherent feature of SAN pacemaker cells and is driven by synergy between If and other ion channels. This work aimed to characterize the connection between membrane currents and their underlying mechanisms in SAN cells. SAN tissues were isolated from C57BL mice and Ca2+ signaling was measured in pacemaker cells within them. A computational model of SAN cells was used to understand the interactions between cell components. Beat interval (BI) was prolonged by 54 ± 18% (N = 16) and 30 ± 9% (N = 21) in response to If blockade, by ivabradine, or sodium current (INa) blockade, by tetrodotoxin, respectively. Combined drug application had a synergistic effect, manifested by a BI prolonged by 143 ± 25% (N = 18). A prolongation in the local Ca2+ release period, which reports on the level of crosstalk within the coupled-clock system, was measured and correlated with the prolongation in BI. The computational model predicted that INa increases in response to If blockade and that this connection is mediated by changes in T and L-type Ca2+ channels. Full article
(This article belongs to the Special Issue Calcium Handling 2.0)
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22 pages, 4439 KiB  
Article
Knockdown of Amyloid Precursor Protein Increases Ion Channel Expression and Alters Ca2+ Signaling Pathways
by Maria Paschou, Danai Liaropoulou, Vasileia Kalaitzaki, Spiros Efthimiopoulos and Panagiota Papazafiri
Int. J. Mol. Sci. 2023, 24(3), 2302; https://doi.org/10.3390/ijms24032302 - 24 Jan 2023
Cited by 3 | Viewed by 2252
Abstract
Although the physiological role of the full-length Amyloid Precursor Protein (APP) and its proteolytic fragments remains unclear, they are definitively crucial for normal synaptic function. Herein, we report that the downregulation of APP in SH-SY5Y cells, using short hairpin RNA (shRNA), alters the [...] Read more.
Although the physiological role of the full-length Amyloid Precursor Protein (APP) and its proteolytic fragments remains unclear, they are definitively crucial for normal synaptic function. Herein, we report that the downregulation of APP in SH-SY5Y cells, using short hairpin RNA (shRNA), alters the expression pattern of several ion channels and signaling proteins that are involved in synaptic and Ca2+ signaling. Specifically, the levels of GluR2 and GluR4 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR) were significantly increased with APP knockdown. Similarly, the expression of the majority of endoplasmic reticulum (ER) residing proteins, such as the ER Ca2+ channels IP3R (Inositol 1,4,5-triphosphate Receptor) and RyR (Ryanodine Receptor), the Ca2+ pump SERCA2 (Sarco/endoplasmic reticulum Ca2+ ATPase 2) and the ER Ca2+ sensor STIM1 (Stromal Interaction Molecule 1) was upregulated. A shift towards the upregulation of p-AKT, p-PP2A, and p-CaMKIV and the downregulation of p-GSK, p-ERK1/2, p-CaMKII, and p-CREB was observed, interconnecting Ca2+ signal transduction from the plasma membrane and ER to the nucleus. Interestingly, we detected reduced responses to several physiological stimuli, with the most prominent being the ineffectiveness of SH-SY5Y/APP- cells to mobilize Ca2+ from the ER upon carbachol-induced Ca2+ release through IP3Rs and RyRs. Our data further support an emerging yet perplexing role of APP within a functional molecular network of membrane and cytoplasmic proteins implicated in Ca2+ signaling. Full article
(This article belongs to the Special Issue Calcium Handling 2.0)
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12 pages, 1615 KiB  
Article
Size-Based Effects of Anthropogenic Ultrafine Particles on Lysosomal TRPML1 Channel and Autophagy in Motoneuron-like Cells
by Silvia Sapienza, Valentina Tedeschi, Barbara Apicella, Francesco Palestra, Carmela Russo, Ilaria Piccialli, Anna Pannaccione, Stefania Loffredo and Agnese Secondo
Int. J. Mol. Sci. 2022, 23(21), 13041; https://doi.org/10.3390/ijms232113041 - 27 Oct 2022
Cited by 3 | Viewed by 1793
Abstract
Background: An emerging body of evidence indicates an association between anthropogenic particulate matter (PM) and neurodegeneration. Although the historical focus of PM toxicity has been on the cardiopulmonary system, ultrafine PM particles can also exert detrimental effects in the brain. However, only a [...] Read more.
Background: An emerging body of evidence indicates an association between anthropogenic particulate matter (PM) and neurodegeneration. Although the historical focus of PM toxicity has been on the cardiopulmonary system, ultrafine PM particles can also exert detrimental effects in the brain. However, only a few studies are available on the harmful interaction between PM and CNS and on the putative pathomechanisms. Methods: Ultrafine PM particles with a diameter < 0.1 μm (PM0.1) and nanoparticles < 20 nm (NP20) were sampled in a lab-scale combustion system. Their effect on cell tracking in the space was studied by time-lapse and high-content microscopy in NSC-34 motor neurons while pHrodo™ Green conjugates were used to detect PM endocytosis. Western blotting analysis was used to quantify protein expression of lysosomal channels (i.e., TRPML1 and TPC2) and autophagy markers. Current-clamp electrophysiology and Fura2-video imaging techniques were used to measure membrane potential, intracellular Ca2+ homeostasis and TRPML1 activity in NSC-34 cells exposed to PM0.1 and NP20. Results: NP20, but not PM0.1, reduced NSC-34 motor neuron movement in the space. Furthermore, NP20 was able to shift membrane potential of motor neurons toward more depolarizing values. PM0.1 and NP20 were able to enter into the cells by endocytosis and exerted mitochondrial toxicity with the consequent stimulation of ROS production. This latter event was sufficient to determine the hyperactivation of the lysosomal channel TRPML1. Consequently, both LC3-II and p62 protein expression increased after 48 h of exposure together with AMPK activation, suggesting an engulfment of autophagy. The antioxidant molecule Trolox restored TRPML1 function and autophagy. Conclusions: Restoring TRPML1 function by an antioxidant agent may be considered a protective mechanism able to reestablish autophagy flux in motor neurons exposed to nanoparticles. Full article
(This article belongs to the Special Issue Calcium Handling 2.0)
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23 pages, 4171 KiB  
Article
α2δ-4 and Cachd1 Proteins Are Regulators of Presynaptic Functions
by Cornelia Ablinger, Clarissa Eibl, Stefanie M. Geisler, Marta Campiglio, Gary J. Stephens, Markus Missler and Gerald J. Obermair
Int. J. Mol. Sci. 2022, 23(17), 9885; https://doi.org/10.3390/ijms23179885 - 31 Aug 2022
Cited by 4 | Viewed by 2758
Abstract
The α2δ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, α [...] Read more.
The α2δ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, α2δ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism. Although the α2δ-4 isoform is predominantly found in the retina with very little expression in the brain, it was recently linked to brain functions. In contrast, Cachd1, a novel α2δ-like protein, shows strong expression in brain, but its function in neurons is not yet known. Therefore, we aimed to investigate the presynaptic functions of α2δ-4 and Cachd1 by expressing individual proteins in cultured hippocampal neurons. Both α2δ-4 and Cachd1 are expressed in the presynaptic membrane and could rescue a severe synaptic defect present in triple knockout/knockdown neurons that lacked the α2δ-1-3 isoforms (α2δ TKO/KD). This observation suggests that presynaptic localization and the regulation of synapse formation in glutamatergic neurons is a general feature of α2δ proteins. In contrast to this redundant presynaptic function, α2δ-4 and Cachd1 differentially regulate the abundance of presynaptic calcium channels and the amplitude of presynaptic calcium transients. These functional differences may be caused by subtle isoform-specific differences in α1-α2δ protein–protein interactions, as revealed by structural homology modelling. Taken together, our study identifies both α2δ-4 and Cachd1 as presynaptic regulators of synapse formation, differentiation, and calcium channel functions that can at least partially compensate for the loss of α2δ-1-3. Moreover, we show that regulating glutamatergic synapse formation and differentiation is a critical and surprisingly redundant function of α2δ and Cachd1. Full article
(This article belongs to the Special Issue Calcium Handling 2.0)
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Review

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17 pages, 661 KiB  
Review
Current Drug Development Overview: Targeting Voltage-Gated Calcium Channels for the Treatment of Pain
by Flavia Tasmin Techera Antunes, Maria Martha Campos, Vanice de Paula Ricardo Carvalho, Claudio Antonio da Silva Junior, Luiz Alexandre Viana Magno, Alessandra Hubner de Souza and Marcus Vinicius Gomez
Int. J. Mol. Sci. 2023, 24(11), 9223; https://doi.org/10.3390/ijms24119223 - 25 May 2023
Cited by 5 | Viewed by 2189
Abstract
Voltage-gated calcium channels (VGCCs) are targeted to treat pain conditions. Since the discovery of their relation to pain processing control, they are investigated to find new strategies for better pain control. This review provides an overview of naturally based and synthetic VGCC blockers, [...] Read more.
Voltage-gated calcium channels (VGCCs) are targeted to treat pain conditions. Since the discovery of their relation to pain processing control, they are investigated to find new strategies for better pain control. This review provides an overview of naturally based and synthetic VGCC blockers, highlighting new evidence on the development of drugs focusing on the VGCC subtypes as well as mixed targets with pre-clinical and clinical analgesic effects. Full article
(This article belongs to the Special Issue Calcium Handling 2.0)
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18 pages, 366 KiB  
Review
Calcium Handling in Inherited Cardiac Diseases: A Focus on Catecholaminergic Polymorphic Ventricular Tachycardia and Hypertrophic Cardiomyopathy
by Stéphane Zaffran, Lilia Kraoua and Hager Jaouadi
Int. J. Mol. Sci. 2023, 24(4), 3365; https://doi.org/10.3390/ijms24043365 - 8 Feb 2023
Cited by 2 | Viewed by 1819
Abstract
Calcium (Ca2+) is the major mediator of cardiac contractile function. It plays a key role in regulating excitation–contraction coupling and modulating the systolic and diastolic phases. Defective handling of intracellular Ca2+ can cause different types of cardiac dysfunction. Thus, the [...] Read more.
Calcium (Ca2+) is the major mediator of cardiac contractile function. It plays a key role in regulating excitation–contraction coupling and modulating the systolic and diastolic phases. Defective handling of intracellular Ca2+ can cause different types of cardiac dysfunction. Thus, the remodeling of Ca2+ handling has been proposed to be a part of the pathological mechanism leading to electrical and structural heart diseases. Indeed, to ensure appropriate electrical cardiac conduction and contraction, Ca2+ levels are regulated by several Ca2+-related proteins. This review focuses on the genetic etiology of cardiac diseases related to calcium mishandling. We will approach the subject by focalizing on two clinical entities: catecholaminergic polymorphic ventricular tachycardia (CPVT) as a cardiac channelopathy and hypertrophic cardiomyopathy (HCM) as a primary cardiomyopathy. Further, this review will illustrate the fact that despite the genetic and allelic heterogeneity of cardiac defects, calcium-handling perturbations are the common pathophysiological mechanism. The newly identified calcium-related genes and the genetic overlap between the associated heart diseases are also discussed in this review. Full article
(This article belongs to the Special Issue Calcium Handling 2.0)
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