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Calcium Signaling in Human Health and Diseases 3.0

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

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 51592

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Dr. Francesco Moccia

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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
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issues "Calcium Signaling in Human Health and Diseases" (https://www.mdpi.com/journal/ijms/special_issues/calcium_signaling) and "Calcium Signaling in Human Health and Diseases 2.0" (https://www.mdpi.com/journal/ijms/special_issues/calcium_signaling2).

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 disruption 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 buffers 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⁺ signaling field, as attested to 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 growing numbers of pathologies are associated with mutations in Ca²⁺-permeable channels and/or Ca²⁺-regulated pathways. We are, therefore, pleased to invite you to participate in this Special Issue, "Calcium Signaling in Human Health and Diseases 3.0", 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

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Keywords

Ca<sup>2+</sup> 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 (13 papers)

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Research

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27 pages, 3825 KiB

Open AccessArticle

TRPM8 as an Anti–Tumoral Target in Prostate Cancer Growth and Metastasis Dissemination

by Guillaume P. Grolez, Giorgia Chinigò, Alexandre Barras, Mehdi Hammadi, Lucile Noyer, Kateryna Kondratska, Etmar Bulk, Thibauld Oullier, Séverine Marionneau-Lambot, Marilyne Le Mée, Stéphanie Rétif, Stéphanie Lerondel, Antonino Bongiovanni, Tullio Genova, Sébastien Roger, Rabah Boukherroub, Albrecht Schwab, Alessandra Fiorio Pla and Dimitra Gkika

Int. J. Mol. Sci. 2022, 23(12), 6672; https://doi.org/10.3390/ijms23126672 - 15 Jun 2022

Cited by 11 | Viewed by 2930

Abstract

In the fight against prostate cancer (PCa), TRPM8 is one of the most promising clinical targets. Indeed, several studies have highlighted that TRPM8 involvement is key in PCa progression because of its impact on cell proliferation, viability, and migration. However, data from the literature are somewhat contradictory regarding the precise role of TRPM8 in prostatic carcinogenesis and are mostly based on in vitro studies. The purpose of this study was to clarify the role played by TRPM8 in PCa progression. We used a prostate orthotopic xenograft mouse model to show that TRPM8 overexpression dramatically limited tumor growth and metastasis dissemination in vivo. Mechanistically, our in vitro data revealed that TRPM8 inhibited tumor growth by affecting the cell proliferation and clonogenic properties of PCa cells. Moreover, TRPM8 impacted metastatic dissemination mainly by impairing cytoskeleton dynamics and focal adhesion formation through the inhibition of the Cdc42, Rac1, ERK, and FAK pathways. Lastly, we proved the in vivo efficiency of a new tool based on lipid nanocapsules containing WS12 in limiting the TRPM8–positive cells’ dissemination at metastatic sites. Our work strongly supports the protective role of TRPM8 on PCa progression, providing new insights into the potential application of TRPM8 as a therapeutic target in PCa treatment. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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17 pages, 5309 KiB

Open AccessArticle

Fibroblast Growth Factor 23 Stimulates Cardiac Fibroblast Activity through Phospholipase C-Mediated Calcium Signaling

by Ting-Wei Lee, Cheng-Chih Chung, Ting-I Lee, Yung-Kuo Lin, Yu-Hsun Kao and Yi-Jen Chen

Int. J. Mol. Sci. 2022, 23(1), 166; https://doi.org/10.3390/ijms23010166 - 23 Dec 2021

Cited by 16 | Viewed by 4024

Abstract

Fibroblast growth factor (FGF)-23 induces hypertrophy and calcium (Ca²⁺) dysregulation in cardiomyocytes, leading to cardiac arrhythmia and heart failure. However, knowledge regarding the effects of FGF-23 on cardiac fibrogenesis remains limited. This study investigated whether FGF-23 modulates cardiac fibroblast activity and explored its underlying mechanisms. We performed MTS analysis, 5-ethynyl-2′-deoxyuridine assay, and wound-healing assay in cultured human atrial fibroblasts without and with FGF-23 (1, 5 and 25 ng/mL for 48 h) to analyze cell proliferation and migration. We found that FGF-23 (25 ng/mL, but not 1 or 5 ng/mL) increased proliferative and migratory abilities of human atrial fibroblasts. Compared to control cells, FGF-23 (25 ng/mL)-treated fibroblasts had a significantly higher Ca²⁺ entry and intracellular inositol 1,4,5-trisphosphate (IP₃) level (assessed by fura-2 ratiometric Ca²⁺ imaging and enzyme-linked immunosorbent assay). Western blot analysis showed that FGF-23 (25 ng/mL)-treated cardiac fibroblasts had higher expression levels of calcium release-activated calcium channel protein 1 (Orai1) and transient receptor potential canonical (TRPC) 1 channel, but similar expression levels of α-smooth muscle actin, collagen type IA1, collagen type Ⅲ, stromal interaction molecule 1, TRPC 3, TRPC6 and phosphorylated-calcium/calmodulin-dependent protein kinase II when compared with control fibroblasts. In the presence of ethylene glycol tetra-acetic acid (a free Ca²⁺ chelator, 1 mM) or U73122 (an inhibitor of phospholipase C, 1 μM), control and FGF-23-treated fibroblasts exhibited similar proliferative and migratory abilities. Moreover, polymerase chain reaction analysis revealed that atrial fibroblasts abundantly expressed FGF receptor 1 but lacked expressions of FGF receptors 2-4. FGF-23 significantly increased the phosphorylation of FGF receptor 1. Treatment with PD166866 (an antagonist of FGF receptor 1, 1 μM) attenuated the effects of FGF-23 on cardiac fibroblast activity. In conclusion, FGF-23 may activate FGF receptor 1 and subsequently phospholipase C/IP₃ signaling pathway, leading to an upregulation of Orai1 and/or TRPC1-mediated Ca²⁺ entry and thus enhancing human atrial fibroblast activity. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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16 pages, 3167 KiB

Open AccessArticle

Characterization of the PLN p.Arg14del Mutation in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

by Beatrice Badone, Carlotta Ronchi, Francesco Lodola, Anika E. Knaust, Arne Hansen, Thomas Eschenhagen and Antonio Zaza

Int. J. Mol. Sci. 2021, 22(24), 13500; https://doi.org/10.3390/ijms222413500 - 16 Dec 2021

Cited by 17 | Viewed by 3011

Abstract

Phospholamban (PLN) is the natural inhibitor of the sarco/endoplasmic reticulum Ca²⁺ ATP-ase (SERCA2a). Heterozygous PLN p.Arg14del mutation is associated with an arrhythmogenic dilated cardiomyopathy (DCM), whose pathogenesis has been attributed to SERCA2a “superinhibition”. Aim: To test in cardiomyocytes (hiPSC-CMs) derived from a PLN p.Arg14del carrier whether (1) Ca²⁺ dynamics and protein localization were compatible with SERCA2a superinhibition and (2) if functional abnormalities could be reverted by pharmacological SERCA2a activation (PST3093). Methods: Ca²⁺ transients (CaT) were recorded at 36 °C in hiPSC-CMs clusters during field stimulation. SERCA2a and PLN where immunolabeled in single hiPSC-CMs. Mutant preparations (MUT) were compared to isogenic wild-type ones (WT), obtained by mutation reversal. Results: WT and MUT differed for the following properties: (1) CaT time to peak (t_peak) and half-time of CaT decay were shorter in MUT; (2) several CaT profiles were identified in WT, “hyperdynamic” ones largely prevailed in MUT; (3) whereas t_peak rate-dependently declined in WT, it was shorter and rate-independent in MUT; (4) diastolic Ca²⁺ rate-dependently accumulated in WT, but not in MUT. When applied to WT, PST3093 turned all the above properties to resemble those of MUT; when applied to MUT, PST3093 had a smaller or negligible effect. Preferential perinuclear SERCA2a-PLN localization was lost in MUT hiPSC-CMs. Conclusions: Functional data converge to argue for PLN p.Arg14del incompetence in inhibiting SERCA2a in the tested case, thus weakening the rationale for therapeutic SERCA2a activation. Mechanisms alternative to SERCA2a superinhibition should be considered in the pathogenesis of DCM, possibly including dysregulation of Ca²⁺-dependent transcription. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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20 pages, 2539 KiB

Open AccessArticle

Regulation of Endoplasmic Reticulum–Mitochondria Tethering and Ca²⁺ Fluxes by TDP-43 via GSK3β

by Caterina Peggion, Maria Lina Massimino, Raphael Severino Bonadio, Federica Lia, Raffaele Lopreiato, Stefano Cagnin, Tito Calì and Alessandro Bertoli

Int. J. Mol. Sci. 2021, 22(21), 11853; https://doi.org/10.3390/ijms222111853 - 1 Nov 2021

Cited by 12 | Viewed by 4131

Abstract

Mitochondria–ER contacts (MERCs), tightly regulated by numerous tethering proteins that act as molecular and functional connections between the two organelles, are essential to maintain a variety of cellular functions. Such contacts are often compromised in the early stages of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). TDP-43, a nuclear protein mainly involved in RNA metabolism, has been repeatedly associated with ALS pathogenesis and other neurodegenerative diseases. Although TDP-43 neuropathological mechanisms are still unclear, the accumulation of the protein in cytoplasmic inclusions may underlie a protein loss-of-function effect. Accordingly, we investigated the impact of siRNA-mediated TDP-43 silencing on MERCs and the related cellular parameters in HeLa cells using GFP-based probes for MERCs quantification and aequorin-based probes for local Ca²⁺ measurements, combined with targeted protein and mRNA profiling. Our results demonstrated that TDP-43 down-regulation decreases MERCs density, thereby remarkably reducing mitochondria Ca²⁺ uptake after ER Ca²⁺ release. Thorough mRNA and protein analyses did not highlight altered expression of proteins involved in MERCs assembly or Ca²⁺-mediated ER–mitochondria cross-talk, nor alterations of mitochondrial density and morphology were observed by confocal microscopy. Further mechanistic inspections, however, suggested that the observed cellular alterations are correlated to increased expression/activity of GSK3β, previously associated with MERCs disruption. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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19 pages, 4524 KiB

Open AccessArticle

Amino Acid-Mediated Intracellular Ca²⁺ Rise Modulates mTORC1 by Regulating the TSC2-Rheb Axis through Ca²⁺/Calmodulin

by Yuna Amemiya, Nao Nakamura, Nao Ikeda, Risa Sugiyama, Chiaki Ishii, Masatoshi Maki, Hideki Shibata and Terunao Takahara

Int. J. Mol. Sci. 2021, 22(13), 6897; https://doi.org/10.3390/ijms22136897 - 27 Jun 2021

Cited by 11 | Viewed by 3151

Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) is a master growth regulator by controlling protein synthesis and autophagy in response to environmental cues. Amino acids, especially leucine and arginine, are known to be important activators of mTORC1 and to promote lysosomal translocation of mTORC1, where mTORC1 is thought to make contact with its activator Rheb GTPase. Although amino acids are believed to exclusively regulate lysosomal translocation of mTORC1 by Rag GTPases, how amino acids increase mTORC1 activity besides regulation of mTORC1 subcellular localization remains largely unclear. Here we report that amino acids also converge on regulation of the TSC2-Rheb GTPase axis via Ca²⁺/calmodulin (CaM). We showed that the amino acid-mediated increase of intracellular Ca²⁺ is important for mTORC1 activation and thereby contributes to the promotion of nascent protein synthesis. We found that Ca²⁺/CaM interacted with TSC2 at its GTPase activating protein (GAP) domain and that a CaM inhibitor reduced binding of CaM with TSC2. The inhibitory effect of a CaM inhibitor on mTORC1 activity was prevented by loss of TSC2 or by an active mutant of Rheb GTPase, suggesting that a CaM inhibitor acts through the TSC2-Rheb axis to inhibit mTORC1 activity. Taken together, in response to amino acids, Ca²⁺/CaM-mediated regulation of the TSC2-Rheb axis contributes to proper mTORC1 activation, in addition to the well-known lysosomal translocation of mTORC1 by Rag GTPases. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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Review

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20 pages, 385 KiB

Open AccessReview

T-Type Calcium Channels: A Mixed Blessing

by Dario Melgari, Anthony Frosio, Serena Calamaio, Gaia A. Marzi, Carlo Pappone and Ilaria Rivolta

Int. J. Mol. Sci. 2022, 23(17), 9894; https://doi.org/10.3390/ijms23179894 - 31 Aug 2022

Cited by 5 | Viewed by 4712

Abstract

The role of T-type calcium channels is well established in excitable cells, where they preside over action potential generation, automaticity, and firing. They also contribute to intracellular calcium signaling, cell cycle progression, and cell fate; and, in this sense, they emerge as key regulators also in non-excitable cells. In particular, their expression may be considered a prognostic factor in cancer. Almost all cancer cells express T-type calcium channels to the point that it has been considered a pharmacological target; but, as the drugs used to reduce their expression are not completely selective, several complications develop, especially within the heart. T-type calcium channels are also involved in a specific side effect of several anticancer agents, that act on microtubule transport, increase the expression of the channel, and, thus, the excitability of sensory neurons, and make the patient more sensitive to pain. This review puts into context the relevance of T-type calcium channels in cancer and in chemotherapy side effects, considering also the cardiotoxicity induced by new classes of antineoplastic molecules. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

30 pages, 2174 KiB

Open AccessReview

Mitochondrial Ca²⁺ Homeostasis: Emerging Roles and Clinical Significance in Cardiac Remodeling

by Dejiu Zhang, Fei Wang, Peifeng Li and Yanyan Gao

Int. J. Mol. Sci. 2022, 23(6), 3025; https://doi.org/10.3390/ijms23063025 - 11 Mar 2022

Cited by 24 | Viewed by 5494

Abstract

Mitochondria are the sites of oxidative metabolism in eukaryotes where the metabolites of sugars, fats, and amino acids are oxidized to harvest energy. Notably, mitochondria store Ca²⁺ and work in synergy with organelles such as the endoplasmic reticulum and extracellular matrix to control the dynamic balance of Ca²⁺ concentration in cells. Mitochondria are the vital organelles in heart tissue. Mitochondrial Ca²⁺ homeostasis is particularly important for maintaining the physiological and pathological mechanisms of the heart. Mitochondrial Ca²⁺ homeostasis plays a key role in the regulation of cardiac energy metabolism, mechanisms of death, oxygen free radical production, and autophagy. The imbalance of mitochondrial Ca²⁺ balance is closely associated with cardiac remodeling. The mitochondrial Ca²⁺ uniporter (mtCU) protein complex is responsible for the uptake and release of mitochondrial Ca²⁺ and regulation of Ca²⁺ homeostasis in mitochondria and consequently, in cells. This review summarizes the mechanisms of mitochondrial Ca²⁺ homeostasis in physiological and pathological cardiac remodeling and the regulatory effects of the mitochondrial calcium regulatory complex on cardiac energy metabolism, cell death, and autophagy, and also provides the theoretical basis for mitochondrial Ca²⁺ as a novel target for the treatment of cardiovascular diseases. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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25 pages, 42106 KiB

Open AccessReview

A Review of Calcineurin Biophysics with Implications for Cardiac Physiology

by Ryan B. Williams and Christopher N. Johnson

Int. J. Mol. Sci. 2021, 22(21), 11565; https://doi.org/10.3390/ijms222111565 - 26 Oct 2021

Cited by 1 | Viewed by 2807

Abstract

Calcineurin, also known as protein phosphatase 2B, is a heterodimeric serine threonine phosphatase involved in numerous signaling pathways. During the past 50 years, calcineurin has been the subject of extensive investigation. Many of its cellular and physiological functions have been described, and the underlying biophysical mechanisms are the subject of active investigation. With the abundance of techniques and experimental designs utilized to study calcineurin and its numerous substrates, it is difficult to reconcile the available information. There have been a plethora of reports describing the role of calcineurin in cardiac disease. However, a physiological role of calcineurin in healthy cardiomyocyte function requires clarification. Here, we review the seminal biophysical and structural details that are responsible for the molecular function and inhibition of calcineurin. We then focus on literature describing the roles of calcineurin in cardiomyocyte physiology and disease. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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11 pages, 776 KiB

Open AccessReview

An Emerging Role for Calcium Signaling in Cancer-Associated Fibroblasts

by Francisco Sadras, Gregory R. Monteith and Sarah J. Roberts-Thomson

Int. J. Mol. Sci. 2021, 22(21), 11366; https://doi.org/10.3390/ijms222111366 - 21 Oct 2021

Cited by 13 | Viewed by 2618

Abstract

Tumors exist in a complex milieu where interaction with their associated microenvironment significantly contributes to disease progression. Cancer-associated fibroblasts (CAFs) are the primary component of the tumor microenvironment and participate in complex bidirectional communication with tumor cells. CAFs support the development of various hallmarks of cancer through diverse processes, including direct cell–cell contact, paracrine signaling, and remodeling and deposition of the extracellular matrix. Calcium signaling is a key second messenger in intra- and inter-cellular signaling pathways that contributes to cancer progression; however, the links between calcium signaling and CAFs are less well-explored. In this review, we put into context the role of calcium signaling in interactions between cancer cells and CAFs, with a focus on migration, proliferation, chemoresistance, and genetic instability. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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18 pages, 1304 KiB

Open AccessReview

MicroRNAs and Calcium Signaling in Heart Disease

by Jae-Ho Park and Changwon Kho

Int. J. Mol. Sci. 2021, 22(19), 10582; https://doi.org/10.3390/ijms221910582 - 30 Sep 2021

Cited by 17 | Viewed by 5410

Abstract

In hearts, calcium (Ca²⁺) signaling is a crucial regulatory mechanism of muscle contraction and electrical signals that determine heart rhythm and control cell growth. Ca²⁺ signals must be tightly controlled for a healthy heart, and the impairment of Ca²⁺ handling proteins is a key hallmark of heart disease. The discovery of microRNA (miRNAs) as a new class of gene regulators has greatly expanded our understanding of the controlling module of cardiac Ca²⁺ cycling. Furthermore, many studies have explored the involvement of miRNAs in heart diseases. In this review, we aim to summarize cardiac Ca²⁺ signaling and Ca²⁺-related miRNAs in pathological conditions, including cardiac hypertrophy, heart failure, myocardial infarction, and atrial fibrillation. We also discuss the therapeutic potential of Ca²⁺-related miRNAs as a new target for the treatment of heart diseases. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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38 pages, 2024 KiB

Open AccessReview

Reactive Oxygen Species and Endothelial Ca²⁺ Signaling: Brothers in Arms or Partners in Crime?

by Sharon Negri, Pawan Faris and Francesco Moccia

Int. J. Mol. Sci. 2021, 22(18), 9821; https://doi.org/10.3390/ijms22189821 - 10 Sep 2021

Cited by 43 | Viewed by 4962

Abstract

An increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca²⁺ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca²⁺ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca²⁺ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca²⁺ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca²⁺ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca²⁺-ATPase 2B, two-pore channels, store-operated Ca²⁺ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca²⁺ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca²⁺]_i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca²⁺ signaling under multiple pathological conditions. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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19 pages, 1353 KiB

Open AccessReview

Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist

by Dania Kallas, Avani Lamba, Thomas M. Roston, Alia Arslanova, Sonia Franciosi, Glen F. Tibbits and Shubhayan Sanatani

Int. J. Mol. Sci. 2021, 22(17), 9293; https://doi.org/10.3390/ijms22179293 - 27 Aug 2021

Cited by 10 | Viewed by 5220

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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9 pages, 4015 KiB

Open AccessHypothesis

Two-Dimensional Interfacial Exchange Diffusion Has the Potential to Augment Spatiotemporal Precision of Ca²⁺ Signaling

by Cornelis van Breemen, Nicola Fameli and Klaus Groschner

Int. J. Mol. Sci. 2022, 23(2), 850; https://doi.org/10.3390/ijms23020850 - 13 Jan 2022

Cited by 1 | Viewed by 1493

Abstract

Nano-junctions between the endoplasmic reticulum and cytoplasmic surfaces of the plasma membrane and other organelles shape the spatiotemporal features of biological Ca²⁺ signals. Herein, we propose that 2D Ca²⁺ exchange diffusion on the negatively charged phospholipid surface lining nano-junctions participates in guiding Ca²⁺ from its source (channel or carrier) to its target (transport protein or enzyme). Evidence provided by in vitro Ca²⁺ flux experiments using an artificial phospholipid membrane is presented in support of the above proposed concept, and results from stochastic simulations of Ca²⁺ trajectories within nano-junctions are discussed in order to substantiate its possible requirements. Finally, we analyze recent literature on Ca²⁺ lipid interactions, which suggests that 2D interfacial Ca²⁺ diffusion may represent an important mechanism of signal transduction in biological systems characterized by high phospholipid surface to aqueous volume ratios. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 3.0)

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