International Journal of Molecular Sciences

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12 pages, 2805 KiB

Open AccessArticle

Calretinin Functions in Malignant Mesothelioma Cells Cannot Be Replaced by the Closely Related Ca²⁺-Binding Proteins Calbindin-D28k and Parvalbumin

by Janine Wörthmüller, Anne Oberson, Valérie Salicio, Walter Blum and Beat Schwaller

Int. J. Mol. Sci. 2018, 19(12), 4015; https://doi.org/10.3390/ijms19124015 - 12 Dec 2018

Cited by 5 | Viewed by 4051

Abstract

Calretinin (CR; CALB2) belonging to the family of EF-hand Ca²⁺-binding proteins (CaBP) is widely used as a positive marker for the identification of human malignant mesothelioma (MM) and functionally was suggested to play a critical role during carcinogenesis of this [...] Read more.

Calretinin (CR; CALB2) belonging to the family of EF-hand Ca²⁺-binding proteins (CaBP) is widely used as a positive marker for the identification of human malignant mesothelioma (MM) and functionally was suggested to play a critical role during carcinogenesis of this highly aggressive asbestos-associated neoplasm. Increasing evidence suggests that CR not only acts as a prototypical Ca²⁺ buffer protein, i.e., limiting the amplitude of Ca²⁺ signals but also as a Ca²⁺ sensor. No studies have yet investigated whether other closely related CaBPs might serve as substitutes for CR’s functions(s) in MM cells. Genetically modified MM cell lines with medium (MSTO-211H and ZL5) or low (SPC111) endogenous CR expression levels were generated that overexpress either CR’s closest homologue calbindin-D28k (CB) or parvalbumin (PV), the latter considered as a “pure” Ca²⁺ buffer protein. After lentiviral shCALB2-mediated CR downregulation, in both MSTO-211H and ZL5 cells expressing CB or PV, the CR deficiency-mediated increase in cell death was not prevented by CB or PV. With respect to proliferation and cell morphology of SPC111 cells, CB was able to substitute for CR, but not for CR’s other functions to promote cell migration or invasion. In conclusion, CR has a likely unique role in MM that cannot be substituted by “similar” CaBPs. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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15 pages, 4315 KiB

Open AccessArticle

Thermodynamic Characterization of the Ca²⁺-Dependent Interaction Between SOUL and ALG-2

by Taisuke Mikasa, Masami Kugo, Seigo Nishimura, Sigeru Taketani, Sumio Ishijima and Ikuko Sagami

Int. J. Mol. Sci. 2018, 19(12), 3802; https://doi.org/10.3390/ijms19123802 - 29 Nov 2018

Cited by 6 | Viewed by 3477

Abstract

SOUL, a heme-binding protein-2 (HEBP-2), interacts with apoptosis-linked gene 2 protein (ALG-2) in a Ca²⁺-dependent manner. To investigate the properties of the interaction of SOUL with ALG-2, we generated several mutants of SOUL and ALG-2 and analyzed the recombinant proteins using [...] Read more.

SOUL, a heme-binding protein-2 (HEBP-2), interacts with apoptosis-linked gene 2 protein (ALG-2) in a Ca²⁺-dependent manner. To investigate the properties of the interaction of SOUL with ALG-2, we generated several mutants of SOUL and ALG-2 and analyzed the recombinant proteins using pulldown assay and isothermal titration calorimetry. The interaction between SOUL and ALG-2 (delta3-23ALG-2) was an exothermic reaction, with 1:1 stoichiometry and high affinity (Kd = 32.4 nM) in the presence of Ca²⁺. The heat capacity change (ΔCp) of the reaction showed a large negative value (−390 cal/K·mol), which suggested the burial of a significant nonpolar surface area or disruption of a hydrogen bond network that was induced by the interaction (or both). One-point mutation of SOUL Phe100 or ALG-2 Trp57 resulted in complete loss of heat change, supporting the essential roles of these residues for the interaction. Nevertheless, a truncated mutant of SOUL1-143 that deleted the domain required for the interaction with ALG-2 Trp57 still showed 1:1 binding to ALG-2 with an endothermic reaction. These results provide a better understanding of the target recognition mechanism and conformational change of SOUL in the interaction with ALG-2. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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16 pages, 3463 KiB

Open AccessArticle

The Effect of Ca²⁺, Lobe-Specificity, and CaMKII on CaM Binding to Na_V1.1

by Jianing Li, Zhiyi Yu, Jianjun Xu, Rui Feng, Qinghua Gao, Tomasz Boczek, Junyan Liu, Zhi Li, Qianhui Wang, Ming Lei, Jian Gong, Huiyuan Hu, Etsuko Minobe, Hong-Long Ji, Masaki Kameyama and Feng Guo

Int. J. Mol. Sci. 2018, 19(9), 2495; https://doi.org/10.3390/ijms19092495 - 23 Aug 2018

Cited by 7 | Viewed by 3751

Abstract

Calmodulin (CaM) is well known as an activator of calcium/calmodulin-dependent protein kinase II (CaMKII). Voltage-gated sodium channels (VGSCs) are basic signaling molecules in excitable cells and are crucial molecular targets for nervous system agents. However, the way in which Ca²⁺/CaM/CaMKII cascade [...] Read more.

Calmodulin (CaM) is well known as an activator of calcium/calmodulin-dependent protein kinase II (CaMKII). Voltage-gated sodium channels (VGSCs) are basic signaling molecules in excitable cells and are crucial molecular targets for nervous system agents. However, the way in which Ca²⁺/CaM/CaMKII cascade modulates Na_V1.1 IQ (isoleucine and glutamine) domain of VGSCs remains obscure. In this study, the binding of CaM, its mutants at calcium binding sites (CaM₁₂, CaM₃₄, and CaM₁₂₃₄), and truncated proteins (N-lobe and C-lobe) to Na_V1.1 IQ domain were detected by pull-down assay. Our data showed that the binding of Ca²⁺/CaM to the Na_V1.1 IQ was concentration-dependent. ApoCaM (Ca²⁺-free form of calmodulin) bound to Na_V1.1 IQ domain preferentially more than Ca²⁺/CaM. Additionally, the C-lobe of CaM was the predominant domain involved in apoCaM binding to Na_V1.1 IQ domain. By contrast, the N-lobe of CaM was predominant in the binding of Ca²⁺/CaM to Na_V1.1 IQ domain. Moreover, CaMKII-mediated phosphorylation increased the binding of Ca²⁺/CaM to Na_V1.1 IQ domain due to one or several phosphorylation sites in T1909, S1918, and T1934 of Na_V1.1 IQ domain. This study provides novel mechanisms for the modulation of Na_V1.1 by the Ca²⁺/CaM/CaMKII axis. For the first time, we uncover the effect of Ca²⁺, lobe-specificity and CaMKII on CaM binding to Na_V1.1. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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13 pages, 3103 KiB

Open AccessArticle

Calcium-Binding Proteins S100A8 and S100A9: Investigation of Their Immune Regulatory Effect in Myeloid Cells

by Jianxin Yang, Jacqueline Anholts, Ulrike Kolbe, Janine A. Stegehuis-Kamp, Frans H. J. Claas and Michael Eikmans

Int. J. Mol. Sci. 2018, 19(7), 1833; https://doi.org/10.3390/ijms19071833 - 21 Jun 2018

Cited by 34 | Viewed by 6594

Abstract

High expression levels of the calcium-binding proteins S100A8 and S100A9 in myeloid cells in kidney transplant rejections are associated with a favorable outcome. Here we investigated the myeloid cell subset expressing these molecules, and their function in inflammatory reactions. Different monocyte subsets were [...] Read more.

High expression levels of the calcium-binding proteins S100A8 and S100A9 in myeloid cells in kidney transplant rejections are associated with a favorable outcome. Here we investigated the myeloid cell subset expressing these molecules, and their function in inflammatory reactions. Different monocyte subsets were sorted from buffy coats of healthy donors and investigated for S100A8 and S100A9 expression. To characterize S100A9high and S100A9low subsets within the CD14+ classical monocyte subset, intracellular S100A9 staining was combined with flow cytometry (FACS) and qPCR profiling. Furthermore, S100A8 and S100A9 were overexpressed by transfection in primary monocyte-derived macrophages and the THP-1 macrophage cell line to investigate the functional relevance. Expression of S100A8 and S100A9 was primarily found in classical monocytes and to a much lower extent in intermediate and non-classical monocytes. All S100A9+ cells expressed human leukocyte antigen—antigen D related (HLA-DR) on their surface. A small population (<3%) of CD14+ CD11b+ CD33+ HLA-DR− cells, characterized as myeloid derived suppressor cells (MDSCs), also expressed S100A9 to high extent. Overexpression of S100A8 and S00A9 in macrophages led to enhanced extracellular reactive oxygen species (ROS) production, as well as elevated mRNA expression of anti-inflammatory IL-10. The results suggest that the calcium-binding proteins S100A8 and S100A9 in myeloid cells have an immune regulatory effect. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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20 pages, 5317 KiB

Open AccessArticle

Interplay between ER Ca²⁺ Binding Proteins, STIM1 and STIM2, Is Required for Store-Operated Ca²⁺ Entry

by Heather A. Nelson, Colin A. Leech, Richard F. Kopp and Michael W. Roe

Int. J. Mol. Sci. 2018, 19(5), 1522; https://doi.org/10.3390/ijms19051522 - 19 May 2018

Cited by 13 | Viewed by 5900

Abstract

Store-operated calcium entry (SOCE), a fundamentally important homeostatic and Ca²⁺ signaling pathway in many types of cells, is activated by the direct interaction of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum (ER) Ca²⁺-binding protein, with Ca²⁺-selective Orai1 [...] Read more.

Store-operated calcium entry (SOCE), a fundamentally important homeostatic and Ca²⁺ signaling pathway in many types of cells, is activated by the direct interaction of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum (ER) Ca²⁺-binding protein, with Ca²⁺-selective Orai1 channels localized in the plasma membrane. While much is known about the regulation of SOCE by STIM1, the role of stromal interaction molecule 2 (STIM2) in SOCE remains incompletely understood. Here, using clustered regularly interspaced short palindromic repeats -CRISPR associated protein 9 (CRISPR-Cas9) genomic editing and molecular imaging, we investigated the function of STIM2 in NIH 3T3 fibroblast and αT3 cell SOCE. We found that deletion of Stim2 expression reduced SOCE by more than 90% in NIH 3T3 cells. STIM1 expression levels were unaffected in the Stim2 null cells. However, quantitative confocal fluorescence imaging demonstrated that in the absence of Stim2 expression, STIM1 did not translocate or form punctae in plasma membrane-associated ER membrane (PAM) junctions following ER Ca²⁺ store depletion. Fluorescence resonance energy transfer (FRET) imaging of intact, living cells revealed that the formation of STIM1 and Orai1 complexes in PAM nanodomains was significantly reduced in the Stim2 knockout cells. Our findings indicate that STIM2 plays an essential role in regulating SOCE in NIH 3T3 and αT3 cells and suggests that dynamic interplay between STIM1 and STIM2 induced by ER Ca²⁺ store discharge is necessary for STIM1 translocation, its interaction with Orai1, and activation of SOCE. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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14 pages, 1716 KiB

Open AccessArticle

GDF11 Modulates Ca²⁺-Dependent Smad2/3 Signaling to Prevent Cardiomyocyte Hypertrophy

by Javier Duran, Mayarling Francisca Troncoso, Daniel Lagos, Sebastian Ramos, Gabriel Marin and Manuel Estrada

Int. J. Mol. Sci. 2018, 19(5), 1508; https://doi.org/10.3390/ijms19051508 - 18 May 2018

Cited by 26 | Viewed by 5636

Abstract

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β family, has been shown to act as a negative regulator in cardiac hypertrophy. Ca²⁺ signaling modulates cardiomyocyte growth; however, the role of Ca²⁺-dependent mechanisms in mediating the effects [...] Read more.

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β family, has been shown to act as a negative regulator in cardiac hypertrophy. Ca²⁺ signaling modulates cardiomyocyte growth; however, the role of Ca²⁺-dependent mechanisms in mediating the effects of GDF11 remains elusive. Here, we found that GDF11 induced intracellular Ca²⁺ increases in neonatal rat cardiomyocytes and that this response was blocked by chelating the intracellular Ca²⁺ with BAPTA-AM or by pretreatment with inhibitors of the inositol 1,4,5-trisphosphate (IP₃) pathway. Moreover, GDF11 increased the phosphorylation levels and luciferase activity of Smad2/3 in a concentration-dependent manner, and the inhibition of IP₃-dependent Ca²⁺ release abolished GDF11-induced Smad2/3 activity. To assess whether GDF11 exerted antihypertrophic effects by modulating Ca²⁺ signaling, cardiomyocytes were exposed to hypertrophic agents (100 nM testosterone or 50 μM phenylephrine) for 24 h. Both treatments increased cardiomyocyte size and [³H]-leucine incorporation, and these responses were significantly blunted by pretreatment with GDF11 over 24 h. Moreover, downregulation of Smad2 and Smad3 with siRNA was accompanied by inhibition of the antihypertrophic effects of GDF11. These results suggest that GDF11 modulates Ca²⁺ signaling and the Smad2/3 pathway to prevent cardiomyocyte hypertrophy. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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17 pages, 11576 KiB

Open AccessArticle

Calsenilin, a Presenilin Interactor, Regulates RhoA Signaling and Neurite Outgrowth

by Hee-Jun Kim, Won-Haeng Lee, Mo-Jong Kim, Sunmee Shin, Byungki Jang, Jae-Bong Park, Wilma Wasco, Joseph D. Buxbaum, Yong-Sun Kim and Eun-Kyoung Choi

Int. J. Mol. Sci. 2018, 19(4), 1196; https://doi.org/10.3390/ijms19041196 - 13 Apr 2018

Cited by 4 | Viewed by 5191

Abstract

Calsenilin modulates A-type potassium channels, regulates presenilin-mediated γ-secretase activity, and represses prodynorphin and c-fos genes expression. RhoA is involved in various cellular functions including proliferation, differentiation, migration, transcription, and regulation of the actin cytoskeleton. Although recent studies demonstrate that calsenilin can directly interact [...] Read more.

Calsenilin modulates A-type potassium channels, regulates presenilin-mediated γ-secretase activity, and represses prodynorphin and c-fos genes expression. RhoA is involved in various cellular functions including proliferation, differentiation, migration, transcription, and regulation of the actin cytoskeleton. Although recent studies demonstrate that calsenilin can directly interact with RhoA and that RhoA inactivation is essential for neuritogenesis, it is uncertain whether there is a link between calsenilin and RhoA-regulated neuritogenesis. Here, we investigated the role of calsenilin in RhoA-regulated neuritogenesis using in vitro and in vivo systems. We found that calsenilin induced RhoA inactivation, which accompanied RhoA phosphorylation and the reduced phosphorylation levels of LIM kinase (LIMK) and cofilin. Interestingly, PC12 cells overexpressing either full-length (FL) or the caspase 3-derived C-terminal fragment (CTF) of calsenilin significantly inactivated RhoA through its interaction with RhoA and p190 Rho GTPase-activating protein (p190RhoGAP). In addition, cells expressing FL and the CTF of calsenilin had increased neurite outgrowth compared to cells expressing the N-terminal fragment (NTF) of calsenilin or vector alone. Moreover, Tat-C3 and Y27632 treatment significantly increased the percentage of neurite-bearing cells, neurite length, and the number of neurites in cells. Finally, calsenilin deficiency in the brains of calsenilin-knockout mice significantly interfered with RhoA inactivation. These findings suggest that calsenilin contributes to neuritogenesis through RhoA inactivation. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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19 pages, 2639 KiB

Open AccessArticle

Nanoluciferase Reporter Gene System Directed by Tandemly Repeated Pseudo-Palindromic NFAT-Response Elements Facilitates Analysis of Biological Endpoint Effects of Cellular Ca²⁺ Mobilization

by Wei Zhang, Terunao Takahara, Takuya Achiha, Hideki Shibata and Masatoshi Maki

Int. J. Mol. Sci. 2018, 19(2), 605; https://doi.org/10.3390/ijms19020605 - 18 Feb 2018

Cited by 5 | Viewed by 6781

Abstract

NFAT is a cytoplasm-localized hyper-phosphorylated transcription factor that is activated through dephosphorylation by calcineurin, a Ca²⁺/calmodulin-dependent phosphatase. A non-palindromic NFAT-response element (RE) found in the IL2 promoter region has been commonly used for a Ca²⁺-response reporter gene system, but [...] Read more.

NFAT is a cytoplasm-localized hyper-phosphorylated transcription factor that is activated through dephosphorylation by calcineurin, a Ca²⁺/calmodulin-dependent phosphatase. A non-palindromic NFAT-response element (RE) found in the IL2 promoter region has been commonly used for a Ca²⁺-response reporter gene system, but requirement of concomitant activation of AP-1 (Fos/Jun) often complicates the interpretation of obtained results. A new nanoluciferase (NanoLuc) reporter gene containing nine-tandem repeats of a pseudo-palindromic NFAT-RE located upstream of the IL8 promoter was designed to monitor Ca²⁺-induced transactivation activity of NFAT in human embryonic kidney (HEK) 293 cells by measuring luciferase activities of NanoLuc and co-expressed firefly luciferase for normalization. Ionomycin treatment enhanced the relative luciferase activity (RLA), which was suppressed by calcineurin inhibitors. HEK293 cells that stably express human STIM1 and Orai1, components of the store-operated calcium entry (SOCE) machinery, gave a much higher RLA by stimulation with thapsigargin, an inhibitor of sarcoplasmic/endoplamic reticulum Ca²⁺-ATPase (SERCA). HEK293 cells deficient in a penta-EF-hand Ca²⁺-binding protein ALG-2 showed a higher RLA value than the parental cells by stimulation with an acetylcholine receptor agonist carbachol. The novel reporter gene system is found to be useful for applications to cell signaling research to monitor biological endpoint effects of cellular Ca²⁺ mobilization. Full article

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14 pages, 2879 KiB

Open AccessArticle

Calbindin D28k-Immunoreactivity in Human Enteric Neurons

by Katharina Zetzmann, Johanna Strehl, Carol Geppert, Stefanie Kuerten, Samir Jabari and Axel Brehmer

Int. J. Mol. Sci. 2018, 19(1), 194; https://doi.org/10.3390/ijms19010194 - 8 Jan 2018

Cited by 16 | Viewed by 6945

Abstract

Calbindin (CALB) is well established as immunohistochemical marker for intrinsic primary afferent neurons in the guinea pig gut. Its expression by numerous human enteric neurons has been demonstrated but little is known about particular types of neurons immunoreactive for CALB. Here we investigated [...] Read more.

Calbindin (CALB) is well established as immunohistochemical marker for intrinsic primary afferent neurons in the guinea pig gut. Its expression by numerous human enteric neurons has been demonstrated but little is known about particular types of neurons immunoreactive for CALB. Here we investigated small and large intestinal wholemount sets of 26 tumor patients in order to evaluate (1) the proportion of CALB⁺ neurons in the total neuron population, (2) the colocalization of CALB with calretinin (CALR), somatostatin (SOM) and vasoactive intestinal peptide (VIP) and (3) the morphology of CALB⁺neurons. CALB⁺neurons represented a minority of myenteric neurons (small intestine: 31%; large intestine: 25%) and the majority of submucosal neurons (between 72 and 95%). In the submucosa, most CALB⁺ neurons co-stained for CALR and VIP (between 69 and 80%) or for SOM (between 20 and 3%). In the myenteric plexus, 85% of CALB⁺neurons did not co-stain with the other markers investigated. An unequivocal correlation between CALB reactivity and neuronal morphology was found for myenteric type III neurons in the small intestine: uniaxonal neurons with long, slender and branched dendrites were generally positive for CALB. Since also other neurons displayed occasional CALB reactivity, this protein is not suited as an exclusive marker for type III neurons. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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Review

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22 pages, 1660 KiB

Open AccessReview

Flux-Independent NMDAR Signaling: Molecular Mediators, Cellular Functions, and Complexities

by Pavel Montes de Oca Balderas

Int. J. Mol. Sci. 2018, 19(12), 3800; https://doi.org/10.3390/ijms19123800 - 29 Nov 2018

Cited by 37 | Viewed by 6586

Abstract

The glutamate (Glu) N-methyl-d-aspartate (NMDA) receptor (NMDAR) plays a critical role in synaptic communication given mainly by its ionotropic function that permeates Ca²⁺. This in turn activates calmodulin that triggers CaMKII, MAPK, CREB, and PI3K pathways, among others. However, [...] Read more.

The glutamate (Glu) N-methyl-d-aspartate (NMDA) receptor (NMDAR) plays a critical role in synaptic communication given mainly by its ionotropic function that permeates Ca²⁺. This in turn activates calmodulin that triggers CaMKII, MAPK, CREB, and PI3K pathways, among others. However, NMDAR signaling is more complex. In the last two decades several groups have shown that the NMDAR also elicits flux-independent signaling (f-iNMDARs). It has been demonstrated that agonist (Glu or NMDA) or co-agonist (Glycine or d-Serine) bindings initiate intracellular events, including conformational changes, exchange of molecular interactions, release of second messengers, and signal transduction, that result in different cellular events including endocytosis, LTD, cell death, and neuroprotection, among others. Interestingly, f-iNMDARs has also been observed in pathological conditions and non-neuronal cells. Here, the molecular and cellular events elicited by these flux-independent actions (non-canonical or metabotropic-like) of the NMDAR are reviewed. Considering the NMDAR complexity, it is possible that these flux-independent events have a more relevant role in intracellular signaling that has been disregarded for decades. Moreover, considering the wide expression and function of the NMDAR in non-neuronal cells and other tissues beyond the nervous system and some evolutionary traits, f-iNMDARs calls for a reconsideration of how we understand the biology of this complex receptor. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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21 pages, 738 KiB

Open AccessReview

Voltage-Dependent Calcium Channels, Calcium Binding Proteins, and Their Interaction in the Pathological Process of Epilepsy

by Jie-Hua Xu and Feng-Ru Tang

Int. J. Mol. Sci. 2018, 19(9), 2735; https://doi.org/10.3390/ijms19092735 - 12 Sep 2018

Cited by 42 | Viewed by 7280

Abstract

As an important second messenger, the calcium ion (Ca²⁺) plays a vital role in normal brain function and in the pathophysiological process of different neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and epilepsy. Ca²⁺ takes part in the [...] Read more.

As an important second messenger, the calcium ion (Ca²⁺) plays a vital role in normal brain function and in the pathophysiological process of different neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and epilepsy. Ca²⁺ takes part in the regulation of neuronal excitability, and the imbalance of intracellular Ca²⁺ is a trigger factor for the occurrence of epilepsy. Several anti-epileptic drugs target voltage-dependent calcium channels (VDCCs). Intracellular Ca²⁺ levels are mainly controlled by VDCCs located in the plasma membrane, the calcium-binding proteins (CBPs) inside the cytoplasm, calcium channels located on the intracellular calcium store (particular the endoplasmic reticulum/sarcoplasmic reticulum), and the Ca²⁺-pumps located in the plasma membrane and intracellular calcium store. So far, while many studies have established the relationship between calcium control factors and epilepsy, the mechanism of various Ca²⁺ regulatory factors in epileptogenesis is still unknown. In this paper, we reviewed the function, distribution, and alteration of VDCCs and CBPs in the central nervous system in the pathological process of epilepsy. The interaction of VDCCs with CBPs in the pathological process of epilepsy was also summarized. We hope this review can provide some clues for better understanding the mechanism of epileptogenesis, and for the development of new anti-epileptic drugs targeting on VDCCs and CBPs. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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20 pages, 3581 KiB

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Unique Ca²⁺-Cycling Protein Abundance and Regulation Sustains Local Ca²⁺ Releases and Spontaneous Firing of Rabbit Sinoatrial Node Cells

by Tatiana M. Vinogradova, Syevda Tagirova (Sirenko) and Edward G. Lakatta

Int. J. Mol. Sci. 2018, 19(8), 2173; https://doi.org/10.3390/ijms19082173 - 25 Jul 2018

Cited by 14 | Viewed by 4586

Abstract

Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) and caused by gradual change of the membrane potential called diastolic depolarization (DD). Submembrane local Ca²⁺ releases (LCR) from sarcoplasmic reticulum (SR) occur during late DD [...] Read more.

Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) and caused by gradual change of the membrane potential called diastolic depolarization (DD). Submembrane local Ca²⁺ releases (LCR) from sarcoplasmic reticulum (SR) occur during late DD and activate an inward Na⁺/Ca²⁺ exchange current, which accelerates the DD rate leading to earlier occurrence of an action potential. A comparison of intrinsic SR Ca²⁺ cycling revealed that, at similar physiological Ca²⁺ concentrations, LCRs are large and rhythmic in permeabilized SANC, but small and random in permeabilized ventricular myocytes (VM). Permeabilized SANC spontaneously released more Ca²⁺ from SR than VM, despite comparable SR Ca²⁺ content in both cell types. In this review we discuss specific patterns of expression and distribution of SR Ca²⁺ cycling proteins (SR Ca²⁺ ATPase (SERCA2), phospholamban (PLB) and ryanodine receptors (RyR)) in SANC and ventricular myocytes. We link ability of SANC to generate larger and rhythmic LCRs with increased abundance of SERCA2, reduced abundance of the SERCA inhibitor PLB. In addition, an increase in intracellular [Ca²⁺] increases phosphorylation of both PLB and RyR exclusively in SANC. The differences in SR Ca²⁺ cycling protein expression between SANC and VM provide insights into diverse regulation of intrinsic SR Ca²⁺ cycling that drives automaticity of SANC. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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18 pages, 1074 KiB

Open AccessReview

Towards Understanding Plant Calcium Signaling through Calmodulin-Like Proteins: A Biochemical and Structural Perspective

by Valentina La Verde, Paola Dominici and Alessandra Astegno

Int. J. Mol. Sci. 2018, 19(5), 1331; https://doi.org/10.3390/ijms19051331 - 30 Apr 2018

Cited by 73 | Viewed by 7711

Abstract

Ca²⁺ ions play a key role in a wide variety of environmental responses and developmental processes in plants, and several protein families with Ca²⁺-binding domains have evolved to meet these needs, including calmodulin (CaM) and calmodulin-like proteins (CMLs). These proteins [...] Read more.

Ca²⁺ ions play a key role in a wide variety of environmental responses and developmental processes in plants, and several protein families with Ca²⁺-binding domains have evolved to meet these needs, including calmodulin (CaM) and calmodulin-like proteins (CMLs). These proteins have no catalytic activity, but rather act as sensor relays that regulate downstream targets. While CaM is well-studied, CMLs remain poorly characterized at both the structural and functional levels, even if they are the largest class of Ca²⁺ sensors in plants. The major structural theme in CMLs consists of EF-hands, and variations in these domains are predicted to significantly contribute to the functional versatility of CMLs. Herein, we focus on recent advances in understanding the features of CMLs from biochemical and structural points of view. The analysis of the metal binding and structural properties of CMLs can provide valuable insight into how such a vast array of CML proteins can coexist, with no apparent functional redundancy, and how these proteins contribute to cellular signaling while maintaining properties that are distinct from CaM and other Ca²⁺ sensors. An overview of the principal techniques used to study the biochemical properties of these interesting Ca²⁺ sensors is also presented. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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16 pages, 822 KiB

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Ca²⁺ Regulation of TRP Ion Channels

by Raquibul Hasan and Xuming Zhang

Int. J. Mol. Sci. 2018, 19(4), 1256; https://doi.org/10.3390/ijms19041256 - 23 Apr 2018

Cited by 67 | Viewed by 7085

Abstract

Ca²⁺ signaling influences nearly every aspect of cellular life. Transient receptor potential (TRP) ion channels have emerged as cellular sensors for thermal, chemical and mechanical stimuli and are major contributors to Ca²⁺ signaling, playing an important role in diverse physiological and [...] Read more.

Ca²⁺ signaling influences nearly every aspect of cellular life. Transient receptor potential (TRP) ion channels have emerged as cellular sensors for thermal, chemical and mechanical stimuli and are major contributors to Ca²⁺ signaling, playing an important role in diverse physiological and pathological processes. Notably, TRP ion channels are also one of the major downstream targets of Ca²⁺ signaling initiated either from TRP channels themselves or from various other sources, such as G-protein coupled receptors, giving rise to feedback regulation. TRP channels therefore function like integrators of Ca²⁺ signaling. A growing body of research has demonstrated different modes of Ca²⁺-dependent regulation of TRP ion channels and the underlying mechanisms. However, the precise actions of Ca²⁺ in the modulation of TRP ion channels remain elusive. Advances in Ca²⁺ regulation of TRP channels are critical to our understanding of the diversified functions of TRP channels and complex Ca²⁺ signaling. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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