A SIMPLE MODEL FOR INTERACTION OF VOLTAGE AND CALCIUM DYNAMICS IN VIRTUAL VENTRICULAR TISSUE

2003 ◽  
Vol 13 (12) ◽  
pp. 3873-3886
Author(s):  
O. V. ASLANIDI ◽  
A. V. HOLDEN
Keyword(s):  
Intracellular Calcium ◽  
Calcium Release ◽  
Cell Model ◽  
Excitation Threshold ◽  
Calcium Dynamics ◽  
Variable Model ◽  
Ventricular Cell ◽  
Calcium Dependent ◽  
Intracellular Ca ◽  
A Site

A simple two-variable model is used to replace the formulation of calcium dynamics in the Luo–Rudy ventricular cell model. Virtual ventricular cell and tissue are developed and validated to reproduce restitution properties and calcium-dependent voltage patterns present in the original model. Basic interactions between the membrane potential and Ca 2+ dynamics in the virtual cell and a strand of the virtual tissue are studied. Intracellular calcium waves can be linked to both action potentials (APs) and delayed afterdepolarizations (DADs). An intracellular calcium wave propagating from the cell interior can induce an AP upon reaching the cell membrane. The voltage and the intracellular Ca 2+ patterns within the same cell can be highly desynchronized. In a one-dimensional strand of the virtual tissue calcium motion is driven by the AP propagation. However, calcium release can be induced upon certain conditions (e.g. Na + overload of the cells), which results in DADs propagating in the wake of AP. Such propagating DADs can reach the excitation threshold, generating a pair of extrasystolic APs. Collision of a propagating AP with a site of elevated intracellular Ca 2+ concentration does not affect the propagation under the normal conditions. Under Na + overload local elevation of the intracellular Ca 2+ leads to generation of an extrasystolic AP, which destroys the original propagating AP.

Aftercontractions and excitation–contraction coupling in rat cardiac muscle

1988 ◽  
Vol 66 (9) ◽  
pp. 1239-1245 ◽  
Author(s):  
Henk E.D.J. ter Keurs ◽  
Peter H. Backx ◽  
Peter P. de Tombe ◽  
Barbara J. Mulder
Keyword(s):  
Cardiac Muscle ◽  
Calcium Release ◽  
Coupled Equations ◽  
Calcium Loading ◽  
Constant Rate ◽  
Method Of Solution ◽  
Intracellular Ca ◽  
Triggered Arrhythmias ◽  
Relative Threshold ◽  
A Site

Calcium loading in cardiac muscle may cause spontaneous contractions (SC). We observed that SC move at a constant rate (Vsc) through isolated rat myocytes and trabeculae. Factors that influence the properties of SC were studied with Nomarsky microscopy and laser diffraction techniques. Myocytes and trabeculae were superfused with Krebs–Henseleit solution (21 °C, pH 7.35; Ca2+, 0.5–7 mM). Vsc in myocytes and within cells of trabeculae ranged between 50 and 150 μm/s. After a train of 3–25 stimuli at 2 Hz, SC in trabeculae started at a site of damage in a region 250 μm in length throughout the muscle. This regional contraction then moved at a constant rate (Vsc) along the length of the muscle. Vsc increased from 0.1 to 15 mm/s with stimulation and Ca2+. Under conditions of calcium loading, spontaneous twitches also occurred throughout the trabeculae, often as triggered arrhythmias. These twitches were always preceded by SC. The range of observed Vsc could be predicted by the Ca2+-induced Ca2+ release hypothesis. We postulated that the contraction propagates by virtue of focal calcium release from the sarcoplasmic reticulum (SR) and we simulated this process together with the processes of diffusion into the cytosol, binding to calmodulin and troponin, sequestration by the SR, and subsequent induction of Ca2+ release from the adjacent SR. The parameters used for the kinetics of binding, release, and sequestration were obtained from those reported in the literature. The minimal and maximal velocities derived from the simulation were 0.09 and 25 mm/s, respectively. The method of solution involved writing the diffusion equation as a difference equation in the spatial coordinates. Thus, bounded, coupled, and ordinary differential equations in time were generated. The coupled equations were solved by using Gear's sixth order predictor–corrector algorithm for stiff equations along with reflective boundaries. These calculations were performed on the Cyber 205 at the University of Calgary. Our results are consistent with the assumptions that Ca2+ loading causes an increase in intracellular Ca2+ concentration, a decrease in the relative threshold for induction of release, and an increase in the amount and rate of Ca2+ released, and hence causes a higher propagation velocity.

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.

Intracellular calcium stores are involved in growth hormone-releasing hormone signal transduction in rat somatotrophs

1999 ◽  
Vol 77 (7) ◽  
pp. 520-528 ◽  
Author(s):  
Audrey Petit ◽  
Catherine Bleicher ◽  
Benoît T Lussier
Keyword(s):  
Growth Hormone ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Calcium Stores ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Intracellular Ca ◽  
Calcium Induced Calcium Release

In rat pituitary somatotrophs, the stimulation of growth hormone secretion by growth hormone-releasing hormone (GHRH) is a Ca2+-dependent event involving Ca2+ influx. The presence of calcium-induced calcium release (CICR) Ca2+ stores has been suggested in these cells. The aim of our study was to demonstrate the presence of CICR stores in rat somatotrophs and to determine their function in GHRH Ca2+ signalling. To this end we measured cytosolic free Ca2+ concentration ([Ca2+]i), using indo-1 in purified rat somatotrophs in primary culture, while altering intracellular Ca2+ stores. Ionomycin (10 µM) or 4-bromo-A23187 (10 µM), used to mobilise organelle-bound Ca2+, raised [Ca2+]i in the absence of extracellular Ca2+. Caffeine (5 to 50 mM), used to mobilise Ca2+ from CICR stores, transiently raised [Ca2+]i in 65% of cells tested. The response to 40 mM caffeine was abolished when Ca2+ stores were depleted, with 1 µM thapsigargin or with 10 µM ryanodine. All cells that responded to 40 mM caffeine responded to 10 nM GHRH. The [Ca2+]i response to 10 nM GHRH was reversible and repeatable. However, the second response was 38% smaller than the first. Ryanodine treatment abolished the reduction in the second [Ca2+]i response, while thapsigargin increased the reduction by 67%. We conclude that rat somatotrophs possess CICR Ca2+ stores and that they account for 30-35% of the GHRH-induced increase in [Ca2+]i, and that their partial depletion is involved in somatotroph desensitization.Key words: somatotrophs, growth hormone-releasing hormone, intracellular calcium, calcium stores, calcium-induced calcium release.

Calcium Dynamics and Generation of Propagating Waves in a Coupled Ensemble of Neurons with Random Connection Strengths

2003 ◽  
Vol 13 (06) ◽  
pp. 1509-1527
Author(s):  
Vladimir E. Bondarenko ◽  
Teresa Ree Chay
Keyword(s):  
Neural Network ◽  
Intracellular Calcium ◽  
Network Model ◽  
Neural Network Model ◽  
Calcium Release ◽  
Experimental Investigations ◽  
Calcium Stores ◽  
Calcium Dynamics ◽  
Intracellular Calcium Store ◽  
Propagating Waves

Recent experimental investigations of the brain show that excitatory α-amino-3-hydroxy-5-methyl-4-isoxazdepropionic acid (AMPA) secreting neurons, inhibitory γ-aminobutyric acid (GABA) secreting neurons, and intracellular calcium play important roles in neural network activities. Specifically, they influence the synchronization and desynchronization of neural ensembles, calcium dynamics in neurons, the generation of waves which propagate along the network. To simulate these types of activities a neural network model is developed which takes into account AMPA and GABA synapses, intracellular calcium, and calcium stores. It is found that the neural network model produces different types of activities, synchronization and desynchronization of neural cells, and propagating waves which are observed in the experiments. The type of activity depends on the type of synapses, connection strengths, values of injected current, and calcium release rate from intracellular calcium store. A mechanism of propagating wave generation based on the reduced connectivity between neurons is proposed.

Modeling action potential generation and propagation in NRK fibroblasts

2004 ◽  
Vol 287 (4) ◽  
pp. C851-C865 ◽  
Author(s):  
J. J. Torres ◽  
L. N. Cornelisse ◽  
E. G. A. Harks ◽  
W. P. M. van Meerwijk ◽  
A. P. R. Theuvenet ◽  
...  
Keyword(s):  
Action Potential ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Cell Transformation ◽  
Rat Kidney ◽  
Potassium Conductance ◽  
Calcium Dynamics ◽  
Starting Point ◽  
Release Analysis ◽  
Intracellular Calcium Dynamics

Normal rat kidney (NRK) fibroblasts change their excitability properties through the various stages of cell proliferation. The present mathematical model has been developed to explain excitability of quiescent (serum deprived) NRK cells. It includes as cell membrane components, on the basis of patch-clamp experiments, an inwardly rectifying potassium conductance ( GKir), an L-type calcium conductance ( GCaL), a leak conductance ( Gleak), an intracellular calcium-activated chloride conductance [ GCl(Ca)], and a gap junctional conductance ( Ggj), coupling neighboring cells in a hexagonal pattern. This membrane model has been extended with simple intracellular calcium dynamics resulting from calcium entry via GCaL channels, intracellular buffering, and calcium extrusion. It reproduces excitability of single NRK cells and cell clusters and intercellular action potential (AP) propagation in NRK cell monolayers. Excitation can be evoked by electrical stimulation, external potassium-induced depolarization, or hormone-induced intracellular calcium release. Analysis shows the roles of the various ion channels in the ultralong (∼30 s) NRK cell AP and reveals the particular role of intracellular calcium dynamics in this AP. We support our earlier conclusion (De Roos A, Willems PH, van Zoelen EJ, and Theuvenet AP. Am J Physiol Cell Physiol 273: C1900–C1907, 1997) that AP generation and propagation may act as a rapid mechanism for the propagation of intracellular calcium waves, thus contributing to fast intercellular calcium signaling. The present model serves as a starting point to further analyze excitability changes during contact inhibition and cell transformation.

Urea signaling to ERK phosphorylation in renal medullary cells requires extracellular calcium but not calcium entry

2001 ◽  
Vol 280 (1) ◽  
pp. F162-F171 ◽  
Author(s):  
Xiao-Yan Yang ◽  
Hongyu Zhao ◽  
Zheng Zhang ◽  
Karin D. Rodland ◽  
Jean-Baptiste Roullet ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Calcium Release ◽  
Calcium Entry ◽  
Extracellular Calcium ◽  
Urea Treatment ◽  
Erk Activation ◽  
Calcium Dependent ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
A Cell

The renal cell line mIMCD3 exhibits markedly upregulated phosphorylation of the extracellular signal-regulated kinase (ERK) 1 and 2 in response to urea treatment (200 mM for 5 min). Previous data have suggested the involvement of a classical protein kinase C (cPKC)-dependent pathway in downstream events related to urea signaling. We now show that urea-inducible ERK activation requires extracellular calcium; unexpectedly, it occurs independently of activation of cPKC isoforms. Pharmacological inhibitors of known intracellular calcium release pathways and extracellular calcium entry pathways fail to inhibit ERK activation by urea. Fura 2 ratiometry was used to assess the effect of urea treatment on intracellular calcium mobilization. In single-cell analyses using subconfluent monolayers and in population-wide analyses using both confluent monolayers and cells in suspension, urea failed to increase intracellular calcium concentration. Taken together, these data indicate that urea-inducible ERK activation requires calcium action but not calcium entry. Although direct evidence is lacking, one possible explanation could include involvement of a calcium-dependent extracellular moiety of a cell surface-associated protein.

scholarly journals Adaptation of the Calcium-dependent Tension Development in Ventricular Cardiomyocytes

2021 ◽  
Vol 7 (2) ◽  
pp. 251-254
Author(s):  
Stephanie Appel ◽  
Tobias Gerach ◽  
Olaf Dössel ◽  
Axel Loewe
Keyword(s):  
Cell Model ◽  
Calcium Transient ◽  
Cellular Level ◽  
Tension Development ◽  
Ventricular Cell ◽  
Calcium Dependent ◽  
Active Contraction ◽  
Cardiac Electromechanics ◽  
Maximum Relative Deviation ◽  
Isometric Twitch

Abstract Today a variety of models describe the physiological behavior of the heart on a cellular level. The intracellular calcium concentration plays an important role, since it is the main driver for the active contraction of the heart. Due to different implementations of the calcium dynamics, simulating cardiac electromechanics can lead to severely different behaviors of the active tension when coupling the same tension model with different electrophysiological models. To handle these variations, we present an optimization tool that adapts the parameters of the most recent, human based tension model. The goal is to generate a physiologically valid tension development when coupled to an electrophysiological cellular model independent of the specifics of that model's calcium transient. In this work, we focus on a ventricular cell model. In order to identify the calcium-sensitive parameters, a sensitivity analysis of the tension model was carried out. In a further step, the cell model was adapted to reproduce the sarcomere length-dependent behavior of troponin C. With a maximum relative deviation of 20.3% per defined characteristic of the tension development, satisfactory results could be obtained for isometric twitch tension. Considering the length-dependent troponin handling, physiological behavior could be reproduced. In conclusion, we propose an algorithm to adapt the tension development model to any calcium transient input to achieve a physiologically valid active contraction on a cellular level. As a proof of concept, the algorithm is successfully applied to one of the most recent human ventricular cell models. This is an important step towards fully coupled electromechanical heart models, which are a valuable tool in personalized health care.

Mediation by Intracellular Calcium-Dependent Signals of Hypoxic Hyperpolarization in Rat Hippocampal CA1 Neurons In Vitro

1997 ◽  
Vol 77 (1) ◽  
pp. 386-392 ◽  
Author(s):  
S. Yamamoto ◽  
E. Tanaka ◽  
H. Higashi
Keyword(s):  
Intracellular Calcium ◽  
Reversal Potential ◽  
Ca1 Neurons ◽  
Calcium Dependent ◽  
Calmodulin Inhibitor ◽  
Hippocampal Ca1 Neurons ◽  
Calmodulin Kinase ◽  
Hippocampal Ca1 ◽  
Intracellular Ca

Yamamoto, S., E. Tanaka and H. Higashi. Mediation by intracellular calcium-dependent signals of hypoxic hyperpolarization in rat hippocampal CA1 neurons in vitro. J. Neurophysiol. 77: 386–392, 1997. In response to oxygen deprivation, CA1 pyramidal neurons show a hyperpolarization (hypoxic hyperpolarization), which is associated with a reduction in neuronal input resistance. The role of extra- and intracellular Ca2+ ions in hypoxic hyperpolarization was investigated. The hypoxic hyperpolarization was significantly depressed by tolbutamide (100 μM); moreover, the response was reversed in its polarity in medium containing tolbutamide (100 μM), low Ca2+ (0.25 mM), and Co2+ (2 mM), suggesting that the hypoxic hyperpolarization is mediated by activation of both ATP-sensitive K+ (KATP) channels and Ca2+-dependent K+ channels. The hypoxic depolarization in medium containing tolbutamide, low Ca2+, and Co2+ is probably due to inhibition of the electrogenic Na+-K+ pump and concomitant accumulation of interstitial K+. Hypoxic hyperpolarizations were depressed in either low Ca2+ (0.25 or 1.25 mM) or high Ca2+ (5 or 7.5 mM) medium (control: 2.5 mM), indicating that there is an optimal extracellular Ca2+ concentration required to producethe hypoxic hyperpolarization. Bis-( o-aminophenoxy)- N,N,N′,N′tetraacetic acid (BAPTA)-AM (50–100 μM), procaine (300 μM), or ryanodine (10 μM) significantly depressed the hypoxic hyperpolarization, suggesting that Ca2+ released from intracellular Ca2+ stores may have an important role in the generation of hypoxic hyperpolarization. The high-affinity calmodulin inhibitor N-(6-amino-hexyl)-5-chloro-1-naphthalenesulfonomide hydrochloride (W-7) (5 μM) completely blocked, whereas the low-affinity calmodulin inhibitor N-(6-aminohexyl)-1-naphthalenesulfonomide hydrochloride (W-5) (50 μM) did not affect, the hypoxic hyperpolarization. The calmodulin inhibitor trifluoperazine (50 μM) also suppressed the hypoxic hyperpolarization. In addition, calcium/calmodulin kinase II inhibitor 1-[N,O-bis(1,5-isoquinol-inesulfonyl)- N-methyl-l-tyrosyl]-4-phenyl-piperazine (KN-62) (10 μM) markedly depressed the amplitude and net outward current of the hypoxic hyperpolarization without affecting the reversal potential. In contrast, neither the myosin light chain kinase inhibitor 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexa-hydro-1,4-diazepin hydrochloride (ML-7) (10 μM) nor the protein kinase A inhibitorN-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide(H-89) (1 μM) significantly altered the hypoxic hyperpolarization. These results suggest that calmodulin kinase II, which is activated by calmodulin, may contribute to the generation of the hypoxic hyperpolarization. In conclusion, the present study indicates that, in the majority of hippocampal CA1 neurons, the hypoxic hyperpolarization is due to activation of both KATP channels and Ca2+-dependent K+ channels.

Effect of γ-secretase inhibitors on muscarinic receptor-mediated calcium signaling in human salivary epithelial cells

2006 ◽  
Vol 291 (1) ◽  
pp. C76-C82 ◽  
Author(s):  
Young S. Oh ◽  
R. James Turner
Keyword(s):  
Intracellular Calcium ◽  
Muscarinic Receptor ◽  
Calcium Release ◽  
Salivary Gland Cell ◽  
Secretase Activity ◽  
Intracellular Ca ◽  
Β Amyloid ◽  
Intracellular Calcium Release ◽  
Interfering Rna ◽  
Considerable Doubt

Altered intracellular Ca2+ signaling has been observed in cells derived from Alzheimer’s disease patients, and a possible link between γ-secretase activity and the content of intracellular Ca2+ stores has been suggested. To test this hypothesis we studied the effects of several γ-secretase inhibitors on muscarinic receptor-mediated intracellular calcium release in the human salivary gland cell line HSG. Although several inhibitors in the peptide aldehyde class partially blocked carbachol-induced Ca2+ transients, these effects did not appear to be due to γ-secretase inhibition, and overall we found no evidence that inhibition of γ-secretase activity had any significant effect on agonist-induced intracellular calcium release in HSG cells. In complementary experiments with presenilin-null cells we found that the reconstitution of γ-secretase activity by transfection with wild-type presenilin 1 likewise had no significant effect on thapsigargin-induced Ca2+ release. In a test of the specific hypothesis that the level of APP intracellular domain (AICD), the intracellular fragment of the β-amyloid precursor protein (APP) resulting from γ-secretase cleavage, can modulate the Ca2+ content of the endoplasmic reticulum, we were unable to demonstrate any effect of APP small interfering RNA on the magnitude of carbachol-induced intracellular calcium release in HSG cells. Together our data cast considerable doubt on the hypothesis that there is a direct link between γ-secretase activity and the content of intracellular Ca2+ stores.

scholarly journals “Ryanopathies” and RyR2 dysfunctions: can we further decipher them using in vitro human disease models?

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Yvonne Sleiman ◽  
Alain Lacampagne ◽  
Albano C. Meli
Keyword(s):  
Intracellular Calcium ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Current Knowledge ◽  
Cell Types ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Cellular Environment ◽  
Intracellular Ca

AbstractThe regulation of intracellular calcium (Ca2+) homeostasis is fundamental to maintain normal functions in many cell types. The ryanodine receptor (RyR), the largest intracellular calcium release channel located on the sarco/endoplasmic reticulum (SR/ER), plays a key role in the intracellular Ca2+ handling. Abnormal type 2 ryanodine receptor (RyR2) function, associated to mutations (ryanopathies) or pathological remodeling, has been reported, not only in cardiac diseases, but also in neuronal and pancreatic disorders. While animal models and in vitro studies provided valuable contributions to our knowledge on RyR2 dysfunctions, the human cell models derived from patients’ cells offer new hope for improving our understanding of human clinical diseases and enrich the development of great medical advances. We here discuss the current knowledge on RyR2 dysfunctions associated with mutations and post-translational remodeling. We then reviewed the novel human cellular technologies allowing the correlation of patient’s genome with their cellular environment and providing approaches for personalized RyR-targeted therapeutics.

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