scholarly journals Nonlinear Dynamic Modeling of 2-Dimensional Interdependent Calcium and Inositol 1,4,5-Trisphosphate in Cardiac Myocyte

2019 ◽  
Vol 14 (1) ◽  
pp. 290-305 ◽  
Author(s):  
N. Singh ◽  
N. Adlakha
Keyword(s):  
Cardiac Myocyte ◽  
Calcium Release ◽  
Feedback Regulation ◽  
Calcium Oscillations ◽  
The Body ◽  
Calcium Dependent ◽  
Coupled Equations ◽  
Calcium Modulation ◽  
Inositol 1,4,5 Trisphosphate ◽  
The Impact

Calcium (Ca2+) and inositol 1,4,5-trisphosphate (IP3) is critically important actors for a vast array of cellular processes. The most significant of the functions is One of the main functions is communication in all parts of the body which is achieved through cell signaling. Abnormalities in Ca2+signaling have been implicated in clinically important conditions such as heart failure and cardiac arrhythmias. We propose a mathematical model which systematically investigates complex Ca2+and IP3dynamics in cardiac myocyte. This two dimensional model is based on calcium-induced calcium release via inositol 1,4,5-trisphosphate receptors and includes calcium modulation of IP3levels through feedback regulation of degradation and production. Forward-Time Centered-Space method has been used to solve the coupled equations. We were able to reproduce the observed oscillatory patterns in Ca2+as well as IP3signals. The model predicts that calcium-dependent production and degradation of IP3is a key mechanism for complex calcium oscillations in cardiac myocyte. The impact and sensitivity of source, leak, diffusion coefficients on both Ca2+and IP3dynamics have been investigated. The results show that the relationship between Ca2+and IP3dynamics is nonlinear.

scholarly journals An Extracellular Redox Signal Triggers Calcium Release and Impacts the Asexual Development of Toxoplasma gondii

2021 ◽  
Vol 11 ◽  
Author(s):  
Eduardo Alves ◽  
Henry J. Benns ◽  
Lilian Magnus ◽  
Caia Dominicus ◽  
Tamás Dobai ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Calcium Release ◽  
Parasitophorous Vacuole ◽  
Human Fibroblasts ◽  
Calcium Dependent ◽  
Intracellular Parasites ◽  
Intracellular Ca ◽  
The Rich ◽  
Sense And Respond ◽  
The Impact

The ability of an organism to sense and respond to environmental redox fluctuations relies on a signaling network that is incompletely understood in apicomplexan parasites such as Toxoplasma gondii. The impact of changes in redox upon the development of this intracellular parasite is not known. Here, we provide a revised collection of 58 genes containing domains related to canonical antioxidant function, with their encoded proteins widely dispersed throughout different cellular compartments. We demonstrate that addition of exogenous H2O2 to human fibroblasts infected with T. gondii triggers a Ca2+ flux in the cytosol of intracellular parasites that can induce egress. In line with existing models, egress triggered by exogenous H2O2 is reliant upon both Calcium-Dependent Protein Kinase 3 and diacylglycerol kinases. Finally, we show that the overexpression a glutaredoxin-roGFP2 redox sensor fusion protein in the parasitophorous vacuole severely impacts parasite replication. These data highlight the rich redox network that exists in T. gondii, evidencing a link between extracellular redox and intracellular Ca2+ signaling that can culminate in parasite egress. Our findings also indicate that the redox potential of the intracellular environment contributes to normal parasite growth. Combined, our findings highlight the important role of redox as an unexplored regulator of parasite biology.

Abstract 14219: Oxidation of PKA-RIα Protects Against Ischemia-reperfusion Injury by Inhibiting Lysosomal-triggered Calcium Release

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jillian N Simon ◽  
BESARTE VRELLAKU ◽  
Stefania Monterisi ◽  
Sandy Chu ◽  
Nadiia Rawlings ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Calcium Release ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Calcium Oscillations ◽  
Pore Channel ◽  
Calcium Stores ◽  
Potent Inducer ◽  
Disulfide Formation ◽  
The Impact

Introduction: Kinase oxidation is a critical signaling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, the regulatory Iα subunit of Protein Kinase A (PKARIα) can be reversibly oxidised, forming interprotein disulfide bonds within the holoenzyme complex. However, the impact of disulfide formation on kinase function, and its influence on PKA signaling in the context of heart disease remains unknown. Methods & Results: Myocardial ischemia-reperfusion (I/R) was found to be a potent inducer of PKARIα disulfide formation in vivo , both in mice and in humans. Using imaging modalities with high spatial and temporal resolution, we found that this conformation did not increase intrinsic PKA catalytic activity, but rather facilitated enhanced AKAP-dependent compartmentation of PKARIα in the adult mouse left ventricular (LV) myocyte, with preferential localization to the lysosome under oxidized conditions (n=38-41 myocytes, N=3 animals, p<0.01). Investigations in isolated LV myocytes revealed disulfide-modified PKARIα to be a significant regulator of lysosomal two pore channel (TPC)-dependent calcium-induced calcium release, with myocytes from ‘redox dead’ PKARIα mice (Cys17Ser) displaying spontaneous sarcoplasmic reticulum calcium release events and pronounced intracellular calcium oscillations. These events were prevented by ryanodine receptor blockade (1 mM tetracaine; n=14, p<0.01), acute depletion of lysosomal calcium stores (100 nM bafilomycin; n=7; p<0.01), or TPC inhibition (5 μM Ned-19; n=9; p<0.05). Absence of I/R-induced disulfide formation in “redox dead” PKARIα mouse hearts resulted in larger infarcts (2-fold increase, p<0.001) and a concomitant reduction in LV contractile recovery (1.6-fold, p<0.001), which could be fully prevented by administering the TPC inhibitor, Ned-19, at the time of reperfusion. Conclusions: Oxidised PKARIα acts as a potent inhibitor of intracellular calcium release in the heart through its redox-dependent interaction with the lysosome. In the setting of I/R, where PKA oxidation is induced, this regulatory mechanism is critical for protecting the heart from injury and offers a novel target for the design of cardioprotective therapeutics.

Abstract 388: Functional Role of Inositol 1,4,5-Trisphosphate Receptors in Cardiac Hypertrophy

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Martha Iveth Garcia
Keyword(s):  
Calcium Release ◽  
Cytosolic Calcium ◽  
The Body ◽  
Calcium Transients ◽  
Expression Levels ◽  
Neonatal Cardiomyocytes ◽  
Adult Rat ◽  
Ventricular Cardiomyocytes ◽  
Calcium Indicator ◽  
Inositol 1,4,5 Trisphosphate

Calcium is a second messenger that is essential for the control of a variety of cellular functions. In the heart, calcium plays an integral role in many cellular processes including energy metabolism, contraction, gene expression, and cell death. The inositol 1,4,5-trisphosphate receptor (IP 3 R) is a calcium channel that is ubiquitously expressed throughout the body. There are three IP 3 R isoforms encoded by separate genes. In the heart, the IP 3 R-2 isoform is reported to being most predominant with regards to both expression levels and functional significance. Several groups have shown that perinuclear IP 3 R-2 may play a key role in the progression of hypertrophy by mediating nuclear calcium release in response to endothelin-1 (ET-1) and angiotensin II. However, the functional roles of IP 3 R-1 and IP 3 R-3 in the heart are essentially unexplored despite measureable expression levels. We hypothesize that all three IP 3 R isoforms can contribute to cytosolic calcium transients and cardiac stress induced by ET-1. As our model we used dissociated neonatal and adult rat ventricular cardiomyocytes. We found readily detectable levels of expression of all three IP 3 Rs in both neonatal and adult rat ventricular cardiomyocytes. We found that in addition to the perinuclear area, all three IP 3 R isoforms were expressed throughout the cardiomyocyte including the sarcoplasmic reticulum. Using isoform specific siRNA, we found that knocking down individual IP 3 Rs did not alter ET-1 induced calcium responses in neonatal cardiomyocytes. However, knocking down all three isoforms abolished the effects of ET-1 on calcium homeostasis. We next tested whether IP 3 Rs mediate nuclear-specific calcium elevations. Using a genetically encoded calcium indicator targeted to the nucleus we were able to specifically discriminate nuclear versus cytosolic calcium transients after ET-1 treatment. Contrary to previous reports, we found no evidence that IP 3 R-mediated calcium release is confined to the nucleus. Our findings that IP 3 R isoforms are functionally redundant in the heart have significant implications for animal models of hypertrophy and human disease.

scholarly journals Ca2+ release via IP3Rs increases RyR mediated Ca2+ spark frequency in ventricular cardiomyocytes without altering spark amplitude and duration

2020 ◽  
Author(s):  
Agnė Tilūnaitė ◽  
David Ladd ◽  
Hilary Hunt ◽  
Christian Soeller ◽  
H. Llewelyn Roderick ◽  
...  
Keyword(s):  
Calcium Release ◽  
Ryanodine Receptors ◽  
Critical Role ◽  
Cardiac Cells ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Inositol 1,4,5 Trisphosphate ◽  
Regulate Cell Growth ◽  
Biochemical Signals ◽  
The Impact

AbstractCalcium plays critical roles in cardiac cells, coupling electrical excitation to mechanical contraction with each heartbeat, while simultaneously mediating biochemical signals that regulate cell growth. While ryanodine receptors (RyRs) are fundamental to generation of elementary calcium release events (sparks) and global calcium elevations that underlie excitation-contraction coupling (ECC), calcium release via inositol 1,4,5-trisphosphate receptors (IP3Rs) is also reported in cardiomyocytes. IP3R calcium release modifies ECC as well as contributing to downstream regulation of hypertrophic gene expression. Recent studies suggest that proximal localisation of IP3Rs with RyRs contributes to their ability to modify Ca2+ handling during ECC. Here we aim to determine the mechanism by which IP3Rs modify Ca2+ handling in cardiomyocytes. We develop a mathematical model incorporating the stochastic behaviour of receptor opening that allows for the parametric tuning of the system to reveal the impact of IP3Rs on spark activation. By testing multiple spark initiation mechanisms, we find that Ca2+ release via IP3Rs result in increased propensity for spark initiation within the cardiac dyad. Our simulations suggest that opening of IP3Rs elevates Ca2+ within the dyad, which increase the probability of spark initiation. Finally, we find that while increasing the number of IP3Rs increases the probability of spark formation, it has little effect on spark amplitude, duration, or overall shape. Our study therefore suggests that IP3R play a critical role in modulating Ca2+ signaling for excitation contraction couplingAuthor summaryWhile Ca2+ release through ryanodine receptors (RyRs) initiates contraction in cardiomyocytes, the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in cardiomyocytes is less clear with Ca2+ release through these channels being invoked in regulating ECC and hypertrophic signalling. RyRs generate cytosolic Ca2+ signals through elemental Ca2+ release events called sparks. The mechanisms by which IP3Rs influence cytosolic Ca2+ are not well understood. We created a 1D model of calcium spark formation in a cardiomyocyte dyad—the primary site of elemental RyR-based calcium release. We investigated possible behaviours of IP3Rs and their interaction with RyRs in generating Ca2+ sparks. We show that for high IP3 concentration, a large number of IP3Rs and high IP3R affinity are required to noticeably affect spark shape. At lower IP3 concentration IP3Rs can increase Ca2+ spark activity, but do not significantly alter the spark shape. Finally our simulations suggest that spark frequency can be reliably increased when IP3Rs activity is such that a small continuous Ca2+ flux is introduced to the dyad to elevate Ca2+, and not via brief but high Ca2+ release from these receptors.

scholarly journals An extracellular redox signal triggers calcium release and impacts the asexual development of Toxoplasma gondii

2021 ◽  
Author(s):  
Eduardo Alves ◽  
Henry J. Benns ◽  
Lilian Magnus ◽  
Caia Dominicus ◽  
Tamás Dobai ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Calcium Release ◽  
Catalytic Domain ◽  
Parasitophorous Vacuole ◽  
Human Fibroblasts ◽  
Calcium Dependent ◽  
Intracellular Ca ◽  
The Rich ◽  
Sense And Respond ◽  
The Impact

AbstractThe ability of an organism to sense and respond to environmental redox fluctuations relies on a signaling network that is incompletely understood in the apicomplexan parasite Toxoplasma gondii. The impact of changes in redox upon the development of this intracellular parasite is not known. Here, we provide a revised collection of 49 genes containing domains related to canonical antioxidant groups, with their encoded proteins widely dispersed throughout different cellular compartments. We demonstrate that addition of exogenous H2O2 to human fibroblasts infected with T. gondii triggers a Ca2+ flux in the cytosol of intracellular parasites that can induce egress. In line with existing models, egress triggered by exogenous H2O2 is reliant upon both Calcium-Dependent Protein Kinase 3 and diacylglycerol kinases. Finally, we show that the overexpression of the active catalytic domain of glutaredoxin in the parasitophorous vacuole severely impacts parasite replication. These data shed light on the rich redox network that exists in T. gondii, evidencing a link between extracellular redox and intracellular Ca2+ signaling that can culminate in parasite egress. Our findings also indicate that the redox potential of the intracellular environment contributes to normal parasite growth. Combined, our findings highlight the important role of redox as an unexplored regulator of parasite biology.

scholarly journals Radial Localization of Inositol 1,4,5-Trisphosphate–sensitive Ca2+ Release Sites in Xenopus Oocytes Resolved by Axial Confocal Linescan Imaging

1999 ◽  
Vol 113 (2) ◽  
pp. 199-213 ◽  
Author(s):  
Nick Callamaras ◽  
Ian Parker
Keyword(s):  
Xenopus Oocytes ◽  
Calcium Release ◽  
Calcium Influx ◽  
Calcium Waves ◽  
Radial Line ◽  
Calcium Dependent ◽  
Inositol 1,4,5 Trisphosphate ◽  
Radial Spread ◽  
Punctate Staining ◽  
Radial Organization

The radial localization and properties of elementary calcium release events (“puffs”) were studied in Xenopus oocytes using a confocal microscope equipped with a piezoelectric focussing unit to allow rapid (&gt;100 Hz) imaging of calcium signals along a radial line into the cell with a spatial resolution of &lt;0.7 μm. Weak photorelease of caged inositol 1,4,5-trisphosphate (InsP3) evoked puffs arising predominantly within a 6-μm thick band located within a few micrometers of the cell surface. Approximately 25% of puffs had a restricted radial spread, consistent with calcium release from a single site. Most puffs, however, exhibited a greater radial spread (3.25 μm), likely involving recruitment of radially neighboring release sites. Calcium waves evoked by just suprathreshold stimuli exhibited radial calcium distributions consistent with inward diffusion of calcium liberated at puff sites, whereas stronger flashes evoked strong, short-latency signals at depths inward from puff sites, indicating deep InsP3-sensitive stores activated at higher concentrations of InsP3. Immunolocalization of InsP3 receptors showed punctate staining throughout a region corresponding to the localization of puffs and subplasmalemmal endoplasmic reticulum. The radial organization of puff sites a few micrometers inward from the plasma membrane may have important consequences for activation of calcium-dependent ion channels and “capacitative” calcium influx. However, on the macroscopic (hundreds of micrometers) scale of global calcium waves, release can be considered to occur primarily within a thin, essentially two-dimensional subplasmalemmal shell.

The Impact of Shariah Governance and Corporate Governance on the Risk Management Practices: Evidence from Local and Foreign Islamic Banks in Malaysia

2018 ◽  
Vol 15 (2) ◽  
pp. 1-20
Author(s):  
Sabri Embi ◽  
Zurina Shafii
Keyword(s):  
Risk Management ◽  
Corporate Governance ◽  
Management Practices ◽  
Principal Component ◽  
T Test ◽  
The Body ◽  
Primary Data ◽  
Islamic Banks ◽  
Shariah Governance ◽  
The Impact

The purpose of this study is to examine the impact of Shariah governance and corporate governance (CG) on the risk management practices (RMPs) of local Islamic banks and foreign Islamic banks operating in Malaysia. The Shariah governance comprises the Shariah review (SR) and Shariah audit (SA) variables. The study also evaluates the level of RMPs, CG, SR, and SA between these two type of banks. With the aid of SPSS version 20, the items for RMPs, CG, SR, and SA were subjected to principal component analysis (PCA). From the PCA, one component or factor was extracted each for the CG, SR, and RMPs while another two factors were extracted for the SA. Primary data was collected using a self-administered survey questionnaire. The questionnaire covers four aspects ; CG, SR, SA, and RMPs. The data received from the 300 usable questionnaires were subjected to correlation and regression analyses as well as an independent t-test. The result of correlation analysis shows that all the four variables have large positive correlations with each other indicating a strong and significant relationship between them. From the regression analysis undertaken, CG, SR, and SA together explained 52.3 percent of the RMPs and CG emerged as the most influential variable that impacts the RMPs. The independent t-test carried out shows that there were significant differences in the CG and SA between the local and foreign Islamic banks. However, there were no significant differences between the two types of the bank in relation to SR and RMPs. The study has contributed to the body of knowledge and is beneficial to academicians, industry players, regulators, and other stakeholders.

Influence of DAFS-25+polizon composition on blood and functional state of liver of steers at fattening

2020 ◽  
pp. 15-18
Author(s):  
Inna R. Kilmetova ◽  
◽  
Igor A. Rodin ◽  
Nazira I. Khayrullina ◽  
Nikolay G. Fenchenko ◽  
...  
Keyword(s):  
Functional State ◽  
White Blood Cells ◽  
Live Weight ◽  
The Body ◽  
Farm Animals ◽  
Control Group ◽  
Standard Diet ◽  
The Impact ◽  
Experimental Group ◽  
Stimulation Of

Summary. The disbalanced feeding and the uneven distribution of micro- and macroelements in the environment leads to a trace element, in particular hypomelanosis. To accelerate the growth and preservation of young farm animals include in the diet of various biological additives and drugs, which include selenium. For stimulation of weight gain in the livestock industry, as well as for the prevention and treatment of pathological processes in addition to micro - and macrouse amino acids, primarily methionine. The aim of this work was to study the influence of composition of DAFS-25+Polizon on morpho-biochemical parameters of blood and functional state of the liver in fattening bulls of black-motley breed in the conditions of the Republic of Bashkortostan. Experiments using were conducted on bull-calves of black-motley breed of the properties in the properties age from 6 to 15 months. The first experimental group during the experiment was additionally given the composition of DAFS-25+Polizon at a dose of 2 mg/kg, the animals of the control group received a standard diet. To assess the impact of the composition DAFS-25+Polizon on metabolism cattle studied morphological and biochemical indicators of blood and conducted histological examination of the liver. It is established that the use of the composition of DAFS-25+Polizon at a dose of 2 mg/kg increases the number of erythrocytes and hemoglobin in the experimental group and reduces the amount of white blood cells. The serum content of total protein, phosphorus and calcium increases in the group of experimental animals. Microscopic examination of the liver revealed no changes in the structure of the organ and hepatocytes in the experimental group, whereas in the control group hemodynamic disorders and dystrophic changes in liver cells were observed. Thus, the use of the composition DAFS-25+Polizon at a dose of 2 mg/kg of live weight in fattening bulls black-and-white breed contributes to the increase of redox processes in the body, stimulation of metabolism, prevent the development of liver disorders of cellular mechanisms of metabolism, optimizes the structure of the liver, which generally provides higher productivity.

Comparative assessment of morphological mechanisms of maintaining structural liver homeostasis in the dynamics of exposure to coal-rock dust and sodium fluoride on the body

2020 ◽  
pp. 189-194
Author(s):  
M. S. Bugaeva ◽  
O. I. Bondarev ◽  
N. N. Mikhailova ◽  
L. G. Gorokhova
Keyword(s):  
Sodium Fluoride ◽  
Morphological Changes ◽  
The Body ◽  
System Level ◽  
Production Factor ◽  
Coal Rock ◽  
The Impact ◽  
Structural Homeostasis ◽  
Rock Dust

Introduction. The impact on the body of such factors of the production environment as coal-rock dust and fluorine compounds leads to certain shift s in strict indicators of homeostasis at the system level. Maintaining the relative constancy of the internal environment of the body is provided by the functional consistency of all organs and systems, the leading of which is the liver. Organ repair plays a crucial role in restoring the structure of genetic material and maintaining normal cell viability. When this mechanism is damaged, the compensatory capabilities of the organ are disrupted, homeostasis is disrupted at the cellular and organizational levels, and the development of the main pathological processes is noted.The aim of the study is to compare the morphological mechanisms of maintaining structural homeostasis of the liver in the dynamics of the impact on the body of coal-rock dust and sodium fluoride.Materials and methods. Experimental studies were conducted on adult white male laboratory rats. Features of morphological mechanisms for maintaining structural homeostasis of the liver in the dynamics of exposure to coal-rock dust and sodium fluoride were studied on experimental models of pneumoconiosis and fluoride intoxication. For histological examination in experimental animals, liver sampling was performed after 1, 3, 6, 9, 12 weeks of the experiment.Results. The specificity of morphological changes in the liver depending on the harmful production factor was revealed. It is shown that chronic exposure to coal-rock dust and sodium fluoride is characterized by the development of similar morphological changes in the liver and its vessels from the predominance of the initial compensatory-adaptive to pronounced violations of the stromal and parenchymal components. Long-term inhalation of coal-rock dust at 1–3 weeks of seeding triggers adaptive mechanisms in the liver in the form of increased functional activity of cells, formation of double-core hepatocytes, activation of immunocompetent cells and endotheliocytes, ensuring the preservation of the parenchyma and the general morphostructure of the organ until the 12th week of the experiment. Exposure to sodium fluoride leads to early disruption of liver compensatory mechanisms and the development of dystrophic changes in the parenchyma with the formation of necrosis foci as early as the 6th week of the experiment.Conclusions. The study of mechanisms for compensating the liver structure in conditions of long-term exposure to coal-rock dust and sodium fluoride, as well as processes that indicate their failure, and the timing of their occurrence, is of theoretical and practical importance for developing recommendations for the timely prevention and correction of pathological conditions developing in employees of the aluminum and coal industry.The authors declare no conflict of interests.

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