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Computational Insights into Calcium Signaling

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Bioinformatics and Systems Biology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 17911

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Special Issue Editors

Dr. Aman Ullah

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Guest Editor

Krasnow Institute for Advanced Study, School of Systems Biology, George Mason University, Fairfax, VA 22030, USA
Interests: calcium dynamics; markov chain models; cell signaling pathways; systems biology; computational modeling

Prof. Dr. Mohsin Saleet Jafri

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Guest Editor

School of Systems Biology and The Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA 22030, USA
Interests: multiscale systems biology; computational biology; bioinformatics; cardiac physiology; immunology; mitochondria; cellular signaling; neuroscience; algorithms; HPC
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Special Issue Information

Dear Colleagues,

Calcium is the ubiquitous second messenger and plays a major role in a variety of cellular functions, both within the same cell and between different cells. These functions include contraction, secretion, cellular transport, fertilization, gene expression, metabolism, disease pathology and others. Calcium is able to control different processes due to its tight regulation, both temporally and spatially. Computational approaches such as modeling and simulation, informatics analysis, molecular simulation, machine learning, signal processing, image analysis, and others have helped scientists gain insights into the complexity of calcium signaling.

This Special Issue of Biomolecules will highlight how computational approaches have been used to understand the mechanisms and consequences of calcium signaling. Contributions in the form of original experimental articles, up-to-date reviews, or short communications are welcome.

Dr. Aman Ullah
Dr. Mohsin Saleet Jafri
Guest Editors

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Keywords

calcium signaling
modeling and simulation
informatics analysis
molecular simulation
machine learning
signal processing
image analysis

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Published Papers (6 papers)

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Research

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32 pages, 16488 KiB

Open AccessEditor’s ChoiceArticle

Local Control Model of a Human Ventricular Myocyte: An Exploration of Frequency-Dependent Changes and Calcium Sparks

by Jerome Anthony E. Alvarez, M. Saleet Jafri and Aman Ullah

Biomolecules 2023, 13(8), 1259; https://doi.org/10.3390/biom13081259 - 17 Aug 2023

Cited by 1 | Viewed by 2732

Abstract

Calcium (Ca²⁺) sparks are the elementary events of excitation–contraction coupling, yet they are not explicitly represented in human ventricular myocyte models. A stochastic ventricular cardiomyocyte human model that adapts to intracellular Ca²⁺ ([Ca²⁺]_i) dynamics, spark regulation, and frequency-dependent changes in the form of locally controlled Ca²⁺ release was developed. The 20,000 CRUs in this model are composed of 9 individual LCCs and 49 RyRs that function as couplons. The simulated action potential duration at 1 Hz steady-state pacing is ~0.280 s similar to human ventricular cell recordings. Rate-dependence experiments reveal that APD shortening mechanisms are largely contributed by the L-type calcium channel inactivation, RyR open fraction, and [Ca²⁺]_myo concentrations. The dynamic slow-rapid-slow pacing protocol shows that RyR open probability during high pacing frequency (2.5 Hz) switches to an adapted “nonconducting” form of Ca²⁺-dependent transition state. The predicted force was also observed to be increased in high pacing, but the SR Ca²⁺ fractional release was lower due to the smaller difference between diastolic and systolic [Ca²⁺]_SR. Restitution analysis through the S1S2 protocol and increased LCC Ca²⁺-dependent activation rate show that the duration of LCC opening helps modulate its effects on the APD restitution at different diastolic intervals. Ultimately, a longer duration of calcium sparks was observed in relation to the SR Ca²⁺ loading at high pacing rates. Overall, this study demonstrates the spontaneous Ca²⁺ release events and ion channel responses throughout various stimuli. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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24 pages, 2648 KiB

Open AccessEditor’s ChoiceArticle

The Role of Ca²⁺ Sparks in Force Frequency Relationships in Guinea Pig Ventricular Myocytes

by Roshan Paudel, Mohsin Saleet Jafri and Aman Ullah

Biomolecules 2022, 12(11), 1577; https://doi.org/10.3390/biom12111577 - 27 Oct 2022

Cited by 2 | Viewed by 2678

Abstract

Calcium sparks are the elementary Ca²⁺ release events in excitation-contraction coupling that underlie the Ca²⁺ transient. The frequency-dependent contractile force generated by cardiac myocytes depends upon the characteristics of the Ca²⁺ transients. A stochastic computational local control model of a guinea pig ventricular cardiomyocyte was developed, to gain insight into mechanisms of force-frequency relationship (FFR). This required the creation of a new three-state RyR2 model that reproduced the adaptive behavior of RyR2, in which the RyR2 channels transition into a different state when exposed to prolonged elevated subspace [Ca²⁺]. The model simulations agree with previous experimental and modeling studies on interval-force relations. Unlike previous common pool models, this local control model displayed stable action potential trains at 7 Hz. The duration and the amplitude of the [Ca²⁺]_myo transients increase in pacing rates consistent with the experiments. The [Ca²⁺]_myo transient reaches its peak value at 4 Hz and decreases afterward, consistent with experimental force-frequency curves. The model predicts, in agreement with previous modeling studies of Jafri and co-workers, diastolic sarcoplasmic reticulum, [Ca²⁺]_sr, and RyR2 adaptation increase with the increased stimulation frequency, producing rising, rather than falling, amplitude of the myoplasmic [Ca²⁺] transients. However, the local control model also suggests that the reduction of the L-type Ca²⁺ current, with an increase in pacing frequency due to Ca²⁺-dependent inactivation, also plays a role in the negative slope of the FFR. In the simulations, the peak Ca²⁺ transient in the FFR correlated with the highest numbers of SR Ca²⁺ sparks: the larger average amplitudes of those sparks, and the longer duration of the Ca²⁺ sparks. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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14 pages, 38118 KiB

Open AccessArticle

Simulation of Calcium Dynamics in Realistic Three-Dimensional Domains

by James Sneyd, John Rugis, Shan Su, Vinod Suresh, Amanda M. Wahl and David I. Yule

Biomolecules 2022, 12(10), 1455; https://doi.org/10.3390/biom12101455 - 11 Oct 2022

Cited by 1 | Viewed by 1749

Abstract

The cytosolic concentration of free calcium ions (

[{Ca}^{2 +}]

) is an important intracellular messenger in most cell types, and the spatial distribution of

[{Ca}^{2 +}]

is often critical. In a salivary gland acinar cell, a [...] Read more.

The cytosolic concentration of free calcium ions (

[{Ca}^{2 +}]

) is an important intracellular messenger in most cell types, and the spatial distribution of

[{Ca}^{2 +}]

is often critical. In a salivary gland acinar cell, a polarised epithelial cell, whose principal function is to transport water and thus secrete saliva,

[{Ca}^{2 +}]

controls the secretion of primary saliva, but increases in

[{Ca}^{2 +}]

are localised to the apical regions of the cell. Hence, any quantitative explanation of how

[{Ca}^{2 +}]

controls saliva secretion must take into careful account the spatial distribution of the various

{Ca}^{2 +}

sources,

{Ca}^{2 +}

sinks, and

{Ca}^{2 +}

-sensitive ion channels. Based on optical slices, we have previously constructed anatomically accurate three-dimensional models of seven salivary gland acinar cells, and thus shown that a model in which

{Ca}^{2 +}

responses are confined to the apical regions of the cell is sufficient to provide a quantitative and predictive explanation of primary saliva secretion. However, reconstruction of such anatomically accurate cells is extremely time consuming and inefficient. Here, we present an alternative, mostly automated method of constructing three-dimensional cells that are approximately anatomically accurate and show that the new construction preserves the quantitative accuracy of the model. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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28 pages, 35141 KiB

Open AccessArticle

Synaptic Plasticity Is Predicted by Spatiotemporal Firing Rate Patterns and Robust to In Vivo-like Variability

by Daniel B. Dorman and Kim T. Blackwell

Biomolecules 2022, 12(10), 1402; https://doi.org/10.3390/biom12101402 - 1 Oct 2022

Cited by 6 | Viewed by 2314

Abstract

Synaptic plasticity, the experience-induced change in connections between neurons, underlies learning and memory in the brain. Most of our understanding of synaptic plasticity derives from in vitro experiments with precisely repeated stimulus patterns; however, neurons exhibit significant variability in vivo during repeated experiences. Further, the spatial pattern of synaptic inputs to the dendritic tree influences synaptic plasticity, yet is not considered in most synaptic plasticity rules. Here, we investigate how spatiotemporal synaptic input patterns produce plasticity with in vivo-like conditions using a data-driven computational model with a plasticity rule based on calcium dynamics. Using in vivo spike train recordings as inputs to different size clusters of spines, we show that plasticity is strongly robust to trial-to-trial variability of spike timing. In addition, we derive general synaptic plasticity rules describing how spatiotemporal patterns of synaptic inputs control the magnitude and direction of plasticity. Synapses that strongly potentiated have greater firing rates and calcium concentration later in the trial, whereas strongly depressing synapses have hiring firing rates early in the trial. The neighboring synaptic activity influences the direction and magnitude of synaptic plasticity, with small clusters of spines producing the greatest increase in synaptic strength. Together, our results reveal that calcium dynamics can unify diverse plasticity rules and reveal how spatiotemporal firing rate patterns control synaptic plasticity. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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Review

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13 pages, 2282 KiB

Open AccessEditor’s ChoiceReview

Calcium Overload and Mitochondrial Metabolism

by Lauren L. Walkon, Jasiel O. Strubbe-Rivera and Jason N. Bazil

Biomolecules 2022, 12(12), 1891; https://doi.org/10.3390/biom12121891 - 17 Dec 2022

Cited by 50 | Viewed by 5313

Abstract

Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates are inhibited in a calcium-titratable manner. While the consequences of extreme calcium overload are well-known, the effects on mitochondrial function in the moderately loaded range remain enigmatic. These observations are associated with changes in the mitochondria ultrastructure and cristae network. The present mini review/perspective follows up on previous studies using well-established cryo–electron microscopy and poses an explanation for the observable depressed ATP synthesis rates in mitochondria during calcium-overloaded states. The results presented herein suggest that the inhibition of oxidative phosphorylation is not caused by a direct decoupling of energy metabolism via the opening of a calcium-sensitive, proteinaceous pore but rather a separate but related calcium-dependent phenomenon. Such inhibition during calcium-overloaded states points towards mitochondrial ultrastructural modifications, enzyme activity changes, or an interplay between both events. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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19 pages, 4619 KiB

Open AccessReview

Modeling Calcium Cycling in the Heart: Progress, Pitfalls, and Challenges

by Zhilin Qu, Dasen Yan and Zhen Song

Biomolecules 2022, 12(11), 1686; https://doi.org/10.3390/biom12111686 - 14 Nov 2022

Cited by 3 | Viewed by 2254

Abstract

Intracellular calcium (Ca) cycling in the heart plays key roles in excitation–contraction coupling and arrhythmogenesis. In cardiac myocytes, the Ca release channels, i.e., the ryanodine receptors (RyRs), are clustered in the sarcoplasmic reticulum membrane, forming Ca release units (CRUs). The RyRs in a CRU act collectively to give rise to discrete Ca release events, called Ca sparks. A cell contains hundreds to thousands of CRUs, diffusively coupled via Ca to form a CRU network. A rich spectrum of spatiotemporal Ca dynamics is observed in cardiac myocytes, including Ca sparks, spark clusters, mini-waves, persistent whole-cell waves, and oscillations. Models of different temporal and spatial scales have been developed to investigate these dynamics. Due to the complexities of the CRU network and the spatiotemporal Ca dynamics, it is challenging to model the Ca cycling dynamics in the cardiac system, particularly at the tissue sales. In this article, we review the progress of modeling of Ca cycling in cardiac systems from single RyRs to the tissue scale, the pros and cons of the current models and different modeling approaches, and the challenges to be tackled in the future. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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