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Calcium Regulation and Sensing

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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 (30 September 2016) | Viewed by 78941

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Dr. ChulHee Kang

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Department of Chemistry, School of Chemical Engineering and Bioengineering, School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Interests: monolignol biosynthesis; enzyme structure and function; biodegradation of organic pollutants; cardiotoxicity of synthetic drugs
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Dear Colleagues,

A very large Ca²⁺ gradient is maintained between the cytosol and sarcoplasmic reticulum/extracellula matrix. Transient elevations in cytoplasmic Ca²⁺ concentrations serve as a second messenger in most eukaryotic cells. Depolarization of cardiac muscle results in the entry of extracellular Ca²⁺ through slow Ca²⁺ channels (dihydropyridine receptors or DHPRs) located in the plasma membrane and transverse tubules. Myoplasmic Ca²⁺ concentrations are then further elevated by Ca²⁺-induced Ca²⁺ release through the Ca²⁺ release channel of the SR (ryanodine receptors or RyRs). The transient elevation of Ca²⁺ activates muscle contraction through its binding to the high affinity Ca²⁺ binding protein, troponin C (TnC), located in the thin filament. Relaxation is induced by the lowering of myoplasmic Ca²⁺ concentrations through the combined action of sarco(endo)plasmic reticulum Ca²⁺ ATPases (SERCAs), which are regulated by phospholamban (PLN) and sarcolipin (SLN), plasma membrane Ca²⁺ ATPases (PMCAs), which are regulated by calmodulin (CaM), and Na⁺/Ca²⁺ exchangers (NCXs). Ca²⁺ is stored in the lumen of the sarcoplasmic reticulum as a complex with an abundant Ca²⁺ binding protein, calsequestrin (CASQ). Functional alterations in this tightly regulated process are directly responsible for many pathophysiological conditions in humans.

We wish to invite articles directly dealing fundamentals of Ca²⁺ regulation, sensing, storage, and related pathophysiologies.

Dr. Chulhee Kang
Guest Editor

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Keywords

DHPR, RyR, TnC, SERCA, PLN, SLN, PMCA, CaM, NcX, CASQ
Arrhythmia, cardiac hypertrophy, heart failure, depressed contractility heart, gene expression, premature death, sudden death
Drug, age-related changes in the E-C coupling process, Ca²⁺ waves
Tachycardia, Bradycardia, Malignant Hyperthermia, Vacuolar Aggregates Myopathy

Published Papers (12 papers)

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Research

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3108 KiB

Open AccessArticle

Down-Regulation of Ca²⁺-Activated K⁺ Channel K_Ca1.1 in Human Breast Cancer MDA-MB-453 Cells Treated with Vitamin D Receptor Agonists

by Anowara Khatun, Mayu Fujimoto, Hiroaki Kito, Satomi Niwa, Takayoshi Suzuki and Susumu Ohya

Int. J. Mol. Sci. 2016, 17(12), 2083; https://doi.org/10.3390/ijms17122083 - 11 Dec 2016

Cited by 12 | Viewed by 5375

Abstract

Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca²⁺-activated K⁺ channel K_Ca1.1 regulates intracellular Ca²⁺ signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR) agonists on the expression and activity of K_Ca1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of K_Ca1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific K_Ca1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in K_Ca1.1 protein expression. These results suggest that K_Ca1.1 is a new downstream target of VDR signaling and the down-regulation of K_Ca1.1 through the transcriptional repression of K_Ca1.1 and enhancement of K_Ca1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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3751 KiB

Open AccessArticle

Dexmedetomidine-Induced Contraction Involves CPI-17 Phosphorylation in Isolated Rat Aortas

by Seong-Ho Ok, Seong-Chun Kwon, Jiseok Baik, Jeong-Min Hong, Jiah Oh, Jeong Yeol Han and Ju-Tae Sohn

Int. J. Mol. Sci. 2016, 17(10), 1663; https://doi.org/10.3390/ijms17101663 - 30 Sep 2016

Cited by 10 | Viewed by 4391

Abstract

Dexmedetomidine, a highly selective α-2 adrenoceptor agonist, produces vasoconstriction, which leads to transiently increased blood pressure. The goal of this study was to investigate specific protein kinases and the associated cellular signal pathways responsible for the increased calcium sensitization induced by dexmedetomidine in isolated rat aortas, with a particular focus on phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17). The effect of Y-27632 and chelerythrine on the dexmedetomidine-induced intracellular calcium concentration ([Ca²⁺]_i) and tension were assessed using fura-2-loaded aortic strips. The effects of rauwolscine, Y-27632, chelerythrine, and ML-7 hydrochloride on the dexmedetomidine-induced phosphorylation of CPI-17 or of the 20-kDa regulatory light chain of myosin (MLC₂₀) were investigated in rat aortic vascular smooth muscle cells. The effects of rauwolscine, Y-27632, and chelerythrine on the membrane translocation of Rho-kinase and protein kinase C (PKC) phosphorylation induced by dexmedetomidine were assessed. Y-27632 and chelerythrine each reduced the slopes of the [Ca²⁺]_i-tension curves of dexmedetomidine-induced contraction, and Y-27632 more strongly reduced these slopes than did chelerythrine. Rauwolscine, Y-27632, chelerythrine, and ML-7 hydrochloride attenuated the dexmedetomidine-induced phosphorylation of CPI-17 and MLC₂₀. Taken together, these results suggest that dexmedetomidine-induced contraction involves calcium sensitization, which appears to be mediated by CPI-17 phosphorylation via Rho-kinase or PKC. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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Open AccessArticle

Characterization of Post-Translational Modifications to Calsequestrins of Cardiac and Skeletal Muscle

by Kevin M. Lewis, Gerhard R. Munske, Samuel S. Byrd, Jeehoon Kang, Hyun-Jai Cho, Eduardo Ríos and ChulHee Kang

Int. J. Mol. Sci. 2016, 17(9), 1539; https://doi.org/10.3390/ijms17091539 - 13 Sep 2016

Cited by 10 | Viewed by 5393

Abstract

Calsequestrin is glycosylated and phosphorylated during its transit to its final destination in the junctional sarcoplasmic reticulum. To determine the significance and universal profile of these post-translational modifications to mammalian calsequestrin, we characterized, via mass spectrometry, the glycosylation and phosphorylation of skeletal muscle calsequestrin from cattle (B. taurus), lab mice (M. musculus) and lab rats (R. norvegicus) and cardiac muscle calsequestrin from cattle, lab rats and humans. On average, glycosylation of skeletal calsequestrin consisted of two N-acetylglucosamines and one mannose (GlcNAc₂Man₁), while cardiac calsequestrin had five additional mannoses (GlcNAc₂Man₆). Skeletal calsequestrin was not phosphorylated, while the C-terminal tails of cardiac calsequestrin contained between zero to two phosphoryls, indicating that phosphorylation of cardiac calsequestrin may be heterogeneous in vivo. Static light scattering experiments showed that the Ca²⁺-dependent polymerization capabilities of native bovine skeletal calsequestrin are enhanced, relative to the non-glycosylated, recombinant isoform, which our crystallographic studies suggest may be due to glycosylation providing a dynamic “guiderail”-like scaffold for calsequestrin polymerization. Glycosylation likely increases a polymerization/depolymerization response to changing Ca²⁺ concentrations, and proper glycosylation, in turn, guarantees both effective Ca²⁺ storage/buffering of the sarcoplasmic reticulum and localization of calsequestrin (Casq) at its target site. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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1178 KiB

Open AccessArticle

Regulation of Intestinal Epithelial Calcium Transport Proteins by Stanniocalcin-1 in Caco2 Cells

by Jinmei Xiang, Rui Guo, Chunyun Wan, Liming Wu, Shijin Yang and Dingzong Guo

Int. J. Mol. Sci. 2016, 17(7), 1095; https://doi.org/10.3390/ijms17071095 - 09 Jul 2016

Cited by 13 | Viewed by 5517

Abstract

Stanniocalcin-1 (STC1) is a calcium and phosphate regulatory hormone. However, the exact molecular mechanisms underlying how STC1 affects Ca²⁺ uptake remain unclear. Here, the expression levels of the calcium transport proteins involved in transcellular transport in Caco2 cells were examined following over-expression or inhibition of STC1. These proteins include the transient receptor potential vanilloid members (TRPV) 5 and 6, the plasma membrane calcium ATPase 1b (PMCA1b), the sodium/calcium exchanger (NCX1), and the vitamin D receptor (VDR). Both gene and protein expressions of TRPV5 and TRPV6 were attenuated in response to over-expression of STC1, and the opposite trend was observed in cells treated with siRNA_STC1. To further investigate the ability of STC1 to influence TRPV6 expression, cells were treated with 100 ng/mL of recombinant human STC1 (rhSTC1) for 4 h following pre-transfection with siRNA_STC1 for 48 h. Intriguingly, the increase in the expression of TRPV6 resulting from siRNA_STC1 was reversed by rhSTC1. No significant effect of STC1 on the expression of PMCA1b, NCX1 or VDR was observed in this study. In conclusion, the effect of STC1 on calcium transport in intestinal epithelia is due to, at least in part, its negative regulation of the epithelial channels TRPV5/6 that mediate calcium influx. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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2615 KiB

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Voltage-Activated Calcium Channels as Functional Markers of Mature Neurons in Human Olfactory Neuroepithelial Cells: Implications for the Study of Neurodevelopment in Neuropsychiatric Disorders

by Héctor Solís-Chagoyán, Edgar Flores-Soto, Jorge Reyes-García, Marcela Valdés-Tovar, Eduardo Calixto, Luis M. Montaño and Gloria Benítez-King

Int. J. Mol. Sci. 2016, 17(6), 941; https://doi.org/10.3390/ijms17060941 - 14 Jun 2016

Cited by 7 | Viewed by 5276

Abstract

In adulthood, differentiation of precursor cells into neurons continues in several brain structures as well as in the olfactory neuroepithelium. Isolated precursors allow the study of the neurodevelopmental process in vitro. The aim of this work was to determine whether the expression of functional Voltage-Activated Ca²⁺ Channels (VACC) is dependent on the neurodevelopmental stage in neuronal cells obtained from the human olfactory epithelium of a single healthy donor. The presence of channel-forming proteins in Olfactory Sensory Neurons (OSN) was demonstrated by immunofluorescent labeling, and VACC functioning was assessed by microfluorometry and the patch-clamp technique. VACC were immunodetected only in OSN. Mature neurons responded to forskolin with a five-fold increase in Ca²⁺. By contrast, in precursor cells, a subtle response was observed. The involvement of VACC in the precursors’ response was discarded for the absence of transmembrane inward Ca²⁺ movement evoked by step depolarizations. Data suggest differential expression of VACC in neuronal cells depending on their developmental stage and also that the expression of these channels is acquired by OSN during maturation, to enable specialized functions such as ion movement triggered by membrane depolarization. The results support that VACC in OSN could be considered as a functional marker to study neurodevelopment. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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Review

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2466 KiB

Open AccessReview

Calcium Dynamics Mediated by the Endoplasmic/Sarcoplasmic Reticulum and Related Diseases

by Florence N. Reddish, Cassandra L. Miller, Rakshya Gorkhali and Jenny J. Yang

Int. J. Mol. Sci. 2017, 18(5), 1024; https://doi.org/10.3390/ijms18051024 - 10 May 2017

Cited by 42 | Viewed by 9328

Abstract

The flow of intracellular calcium (Ca²⁺) is critical for the activation and regulation of important biological events that are required in living organisms. As the major Ca²⁺ repositories inside the cell, the endoplasmic reticulum (ER) and the sarcoplasmic reticulum (SR) of muscle cells are central in maintaining and amplifying the intracellular Ca²⁺ signal. The morphology of these organelles, along with the distribution of key calcium-binding proteins (CaBPs), regulatory proteins, pumps, and receptors fundamentally impact the local and global differences in Ca²⁺ release kinetics. In this review, we will discuss the structural and morphological differences between the ER and SR and how they influence localized Ca²⁺ release, related diseases, and the need for targeted genetically encoded calcium indicators (GECIs) to study these events. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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916 KiB

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Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca²⁺

by Juan Zou, Jason Y. Jiang and Jenny J. Yang

Int. J. Mol. Sci. 2017, 18(3), 672; https://doi.org/10.3390/ijms18030672 - 21 Mar 2017

Cited by 7 | Viewed by 8384

Abstract

Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca²⁺ was reported to exhibit direct activation and modulation via an allosteric site, the identification of those binding sites was challenged by weak binding. Herein, we review the discovery of extracellular Ca²⁺ in regulation of mGluRs, summarize the recent developments in probing Ca²⁺ binding and its co-regulation of the receptor based on structural and biochemical analysis, and discuss the molecular basis for Ca²⁺ to regulate various classes of drug action as well as its importance as an allosteric modulator in mGluRs. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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3194 KiB

Open AccessReview

Calcium Signaling in Interstitial Cells: Focus on Telocytes

by Beatrice Mihaela Radu, Adela Banciu, Daniel Dumitru Banciu, Mihai Radu, Dragos Cretoiu and Sanda Maria Cretoiu

Int. J. Mol. Sci. 2017, 18(2), 397; https://doi.org/10.3390/ijms18020397 - 13 Feb 2017

Cited by 26 | Viewed by 6191

Abstract

In this review, we describe the current knowledge on calcium signaling pathways in interstitial cells with a special focus on interstitial cells of Cajal (ICCs), interstitial Cajal-like cells (ICLCs), and telocytes. In detail, we present the generation of Ca²⁺ oscillations, the inositol triphosphate (IP₃)/Ca²⁺ signaling pathway and modulation exerted by cytokines and vasoactive agents on calcium signaling in interstitial cells. We discuss the physiology and alterations of calcium signaling in interstitial cells, and in particular in telocytes. We describe the physiological contribution of calcium signaling in interstitial cells to the pacemaking activity (e.g., intestinal, urinary, uterine or vascular pacemaking activity) and to the reproductive function. We also present the pathological contribution of calcium signaling in interstitial cells to the aortic valve calcification or intestinal inflammation. Moreover, we summarize the current knowledge of the role played by calcium signaling in telocytes in the uterine, cardiac and urinary physiology, and also in various pathologies, including immune response, uterine and cardiac pathologies. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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718 KiB

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Astrocytic Pathological Calcium Homeostasis and Impaired Vesicle Trafficking in Neurodegeneration

by Nina Vardjan, Alexej Verkhratsky and Robert Zorec

Int. J. Mol. Sci. 2017, 18(2), 358; https://doi.org/10.3390/ijms18020358 - 08 Feb 2017

Cited by 24 | Viewed by 5572

Abstract

Although the central nervous system (CNS) consists of highly heterogeneous populations of neurones and glial cells, clustered into diverse anatomical regions with specific functions, there are some conditions, including alertness, awareness and attention that require simultaneous, coordinated and spatially homogeneous activity within a large area of the brain. During such events, the brain, representing only about two percent of body mass, but consuming one fifth of body glucose at rest, needs additional energy to be produced. How simultaneous energy procurement in a relatively extended area of the brain takes place is poorly understood. This mechanism is likely to be impaired in neurodegeneration, for example in Alzheimer’s disease, the hallmark of which is brain hypometabolism. Astrocytes, the main neural cell type producing and storing glycogen, a form of energy in the brain, also hold the key to metabolic and homeostatic support in the central nervous system and are impaired in neurodegeneration, contributing to the slow decline of excitation-energy coupling in the brain. Many mechanisms are affected, including cell-to-cell signalling. An important question is how changes in cellular signalling, a process taking place in a rather short time domain, contribute to the neurodegeneration that develops over decades. In this review we focus initially on the slow dynamics of Alzheimer’s disease, and on the activity of locus coeruleus, a brainstem nucleus involved in arousal. Subsequently, we overview much faster processes of vesicle traffic and cytosolic calcium dynamics, both of which shape the signalling landscape of astrocyte-neurone communication in health and neurodegeneration. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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1161 KiB

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Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis

by Christian A. Di Buduo, Alessandra Balduini and Francesco Moccia

Int. J. Mol. Sci. 2016, 17(12), 2055; https://doi.org/10.3390/ijms17122055 - 08 Dec 2016

Cited by 11 | Viewed by 7981

Abstract

Store-Operated Calcium Entry (SOCE) is a universal calcium (Ca²⁺) influx mechanism expressed by several different cell types. It is now known that Stromal Interaction Molecule (STIM), the Ca²⁺ sensor of the intracellular compartments, together with Orai and Transient Receptor Potential Canonical (TRPC), the subunits of Ca²⁺ permeable channels on the plasma membrane, cooperate in regulating multiple cellular functions as diverse as proliferation, differentiation, migration, gene expression, and many others, depending on the cell type. In particular, a growing body of evidences suggests that a tight control of SOCE expression and function is achieved by megakaryocytes along their route from hematopoietic stem cells to platelet production. This review attempts to provide an overview about the SOCE dynamics in megakaryocyte development, with a focus on most recent findings related to its involvement in physiological and pathological thrombopoiesis. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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1774 KiB

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Calcium Dyshomeostasis in Tubular Aggregate Myopathy

by Jong-Mok Lee and Satoru Noguchi

Int. J. Mol. Sci. 2016, 17(11), 1952; https://doi.org/10.3390/ijms17111952 - 22 Nov 2016

Cited by 11 | Viewed by 7812

Abstract

Calcium is a crucial mediator of cell signaling in skeletal muscles for basic cellular functions and specific functions, including contraction, fiber-type differentiation and energy production. The sarcoplasmic reticulum (SR) is an organelle that provides a large supply of intracellular Ca²⁺ in myofibers. Upon excitation, it releases Ca²⁺ into the cytosol, inducing contraction of myofibrils. During relaxation, it takes up cytosolic Ca²⁺ to terminate the contraction. During exercise, Ca²⁺ is cycled between the cytosol and the SR through a system by which the Ca²⁺ pool in the SR is restored by uptake of extracellular Ca²⁺ via a specific channel on the plasma membrane. This channel is called the store-operated Ca²⁺ channel or the Ca²⁺ release-activated Ca²⁺ channel. It is activated by depletion of the Ca²⁺ store in the SR by coordination of two main molecules: stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (ORAI1). Recently, myopathies with a dominant mutation in these genes have been reported and the pathogenic mechanism of such diseases have been proposed. This review overviews the calcium signaling in skeletal muscles and role of store-operated Ca²⁺ entry in calcium homeostasis. Finally, we discuss the phenotypes and the pathomechanism of myopathies caused by mutations in the STIM1 and ORAI1 genes. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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1663 KiB

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The Control of Calcium Metabolism in Zebrafish (Danio rerio)

by Chia-Hao Lin and Pung-Pung Hwang

Int. J. Mol. Sci. 2016, 17(11), 1783; https://doi.org/10.3390/ijms17111783 - 26 Oct 2016

Cited by 47 | Viewed by 7005

Abstract

Zebrafish is an emerging model for the research of body fluid ionic homeostasis. In this review, we focus on current progress on the regulation of Ca²⁺ uptake in the context of Ca²⁺ sensing and hormonal regulation in zebrafish. Na⁺-K⁺-ATPase-rich cells (NaRCs), the specialized ionocytes in the embryonic skin and adult gills, play a dominant role in Ca²⁺ uptake in zebrafish. Transepithelial Ca²⁺ transport in NaRC, through apical epithelial Ca²⁺ channels (ECaC), basolateral plasma membrane Ca²⁺-ATPase (PMCA), and Na⁺/Ca²⁺ exchanger (NCX), is analogous to mammalian renal and intestinal Ca²⁺-absorption cells. Several hormones were demonstrated to differentially regulate Ca²⁺ uptake through modulating the expression of Ca²⁺ transporters and/or the proliferation/differentiation of NaRC in zebrafish. In addition, the counterbalance among these hormones is associated with the maintenance of body fluid Ca²⁺ homeostasis. Calcium-sensing receptor (CaSR) is expressed in several hormone-secreting tissues in zebrafish, and activated CaSR differentially controls calciotropic hormones. The major principles of Ca²⁺ transport and the hormonal control appear to be conserved from zebrafish to other vertebrates including mammals. The new knowledge gained from zebrafish studies provides new insights into the related issues in vertebrates. Full article

(This article belongs to the Special Issue Calcium Regulation and Sensing)

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