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Studying dyadic structure – function relationships: a review of current modeling approaches and new insights into Ca 2+ (mis)handling

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ABSTRACT

Excitation–contraction coupling in cardiac myocytes requires calcium influx through L-type calcium channels in the sarcolemma, which gates calcium release through sarcoplasmic reticulum ryanodine receptors in a process known as calcium-induced calcium release, producing a myoplasmic calcium transient and enabling cardiomyocyte contraction. The spatio-temporal dynamics of calcium release, buffering, and reuptake into the sarcoplasmic reticulum play a central role in excitation–contraction coupling in both normal and diseased cardiac myocytes. However, further quantitative understanding of these cells’ calcium machinery and the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease requires accurate knowledge of cardiac ultrastructure, protein distribution and subcellular function. As current imaging techniques are limited in spatial resolution, limiting insight into changes in calcium handling, computational models of excitation–contraction coupling have been increasingly employed to probe these structure–function relationships. This review will focus on the development of structural models of cardiac calcium dynamics at the subcellular level, orienting the reader broadly towards the development of models of subcellular calcium handling in cardiomyocytes. Specific focus will be given to progress in recent years in terms of multi-scale modeling employing resolved spatial models of subcellular calcium machinery. A review of the state-of-the-art will be followed by a review of emergent insights into calcium-dependent etiologies in heart disease and, finally, we will offer a perspective on future directions for related computational modeling and simulation efforts.

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Representation of the next generation of subcellular computational models, from left: super-resolution light microscopy permits resolution of the morphology of ryanodine receptor (RyR) clusters, which can be incorporated into synthetic geometries of the calcium release unit (CRU). Using these synthetic geometries, one can easily and systematically alter the distribution of RyRs, the shape and volume of the junctional SR (jSR) and network SR (nSR), and the cleft volume, and begin to analyze the different contributions quantitatively, permitting query into how spark fidelity is affected by RyR density, by cluster breakup, by cleft height, or by small and narrow jSR (local depletion of Ca). On the other hand (from right), these synthetic geometries neglect the potentially important role played by detailed and realistic CRU structures, which can now be obtained from electron tomography. (Images reproduced from Hake et al.58 with permission.)
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f4-10.1177_1179546817698602: Representation of the next generation of subcellular computational models, from left: super-resolution light microscopy permits resolution of the morphology of ryanodine receptor (RyR) clusters, which can be incorporated into synthetic geometries of the calcium release unit (CRU). Using these synthetic geometries, one can easily and systematically alter the distribution of RyRs, the shape and volume of the junctional SR (jSR) and network SR (nSR), and the cleft volume, and begin to analyze the different contributions quantitatively, permitting query into how spark fidelity is affected by RyR density, by cluster breakup, by cleft height, or by small and narrow jSR (local depletion of Ca). On the other hand (from right), these synthetic geometries neglect the potentially important role played by detailed and realistic CRU structures, which can now be obtained from electron tomography. (Images reproduced from Hake et al.58 with permission.)

Mentions: Correlated light and electron microscopic (CLEM) imaging is a powerful method wherein each imaging mode provides unique information for dissecting cell and tissue function at high resolution.88 Other recent approaches have combined fluorescence resonance energy transfer (FRET), simulated-annealing (a form of combinatorial optimization), cryo-electron microscopy, and crystallographic data to locate a biosensor peptide bound to RyR Ca channels89 and have targeted a new sensitive Ca biosensor to the junctional space, where it co-localized with t-tubules and RyRs, allowing selective visualization and measurement of nanodomain Ca dynamics in intact cells.90 These multi-scale experimental and imaging approaches will offer mechanistic insights into CRU RyR operations in health and in disease states, and additionally offer potential for future inclusion in mechanistic computational modeling. Furthermore, emerging super-resolution single-molecule localization microscopy (SMLM) techniques offer an order of magnitude improvement over resolution of conventional fluorescence light microscopy; nanometer-scale distributions of multiple molecular targets can be resolved. In conjunction with the next generation of electron microscopy, SMLM has allowed the visualization and quantification of intricate t-tubule morphologies within large areas of muscle cells at unprecedented levels of detail, as recently reviewed.91 Novel and emerging imaging methods will enable the incorporation of detailed subcellular structural and functional information into the next generation of computational models (Figure 4), providing entirely new insights into the ion dynamics underpinning excitation and contraction in the heart, as well as the ways in which the system can fail in cardiac disease.


Studying dyadic structure – function relationships: a review of current modeling approaches and new insights into Ca 2+ (mis)handling
Representation of the next generation of subcellular computational models, from left: super-resolution light microscopy permits resolution of the morphology of ryanodine receptor (RyR) clusters, which can be incorporated into synthetic geometries of the calcium release unit (CRU). Using these synthetic geometries, one can easily and systematically alter the distribution of RyRs, the shape and volume of the junctional SR (jSR) and network SR (nSR), and the cleft volume, and begin to analyze the different contributions quantitatively, permitting query into how spark fidelity is affected by RyR density, by cluster breakup, by cleft height, or by small and narrow jSR (local depletion of Ca). On the other hand (from right), these synthetic geometries neglect the potentially important role played by detailed and realistic CRU structures, which can now be obtained from electron tomography. (Images reproduced from Hake et al.58 with permission.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5392018&req=5

f4-10.1177_1179546817698602: Representation of the next generation of subcellular computational models, from left: super-resolution light microscopy permits resolution of the morphology of ryanodine receptor (RyR) clusters, which can be incorporated into synthetic geometries of the calcium release unit (CRU). Using these synthetic geometries, one can easily and systematically alter the distribution of RyRs, the shape and volume of the junctional SR (jSR) and network SR (nSR), and the cleft volume, and begin to analyze the different contributions quantitatively, permitting query into how spark fidelity is affected by RyR density, by cluster breakup, by cleft height, or by small and narrow jSR (local depletion of Ca). On the other hand (from right), these synthetic geometries neglect the potentially important role played by detailed and realistic CRU structures, which can now be obtained from electron tomography. (Images reproduced from Hake et al.58 with permission.)
Mentions: Correlated light and electron microscopic (CLEM) imaging is a powerful method wherein each imaging mode provides unique information for dissecting cell and tissue function at high resolution.88 Other recent approaches have combined fluorescence resonance energy transfer (FRET), simulated-annealing (a form of combinatorial optimization), cryo-electron microscopy, and crystallographic data to locate a biosensor peptide bound to RyR Ca channels89 and have targeted a new sensitive Ca biosensor to the junctional space, where it co-localized with t-tubules and RyRs, allowing selective visualization and measurement of nanodomain Ca dynamics in intact cells.90 These multi-scale experimental and imaging approaches will offer mechanistic insights into CRU RyR operations in health and in disease states, and additionally offer potential for future inclusion in mechanistic computational modeling. Furthermore, emerging super-resolution single-molecule localization microscopy (SMLM) techniques offer an order of magnitude improvement over resolution of conventional fluorescence light microscopy; nanometer-scale distributions of multiple molecular targets can be resolved. In conjunction with the next generation of electron microscopy, SMLM has allowed the visualization and quantification of intricate t-tubule morphologies within large areas of muscle cells at unprecedented levels of detail, as recently reviewed.91 Novel and emerging imaging methods will enable the incorporation of detailed subcellular structural and functional information into the next generation of computational models (Figure 4), providing entirely new insights into the ion dynamics underpinning excitation and contraction in the heart, as well as the ways in which the system can fail in cardiac disease.

View Article: PubMed Central - PubMed

ABSTRACT

Excitation–contraction coupling in cardiac myocytes requires calcium influx through L-type calcium channels in the sarcolemma, which gates calcium release through sarcoplasmic reticulum ryanodine receptors in a process known as calcium-induced calcium release, producing a myoplasmic calcium transient and enabling cardiomyocyte contraction. The spatio-temporal dynamics of calcium release, buffering, and reuptake into the sarcoplasmic reticulum play a central role in excitation–contraction coupling in both normal and diseased cardiac myocytes. However, further quantitative understanding of these cells’ calcium machinery and the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease requires accurate knowledge of cardiac ultrastructure, protein distribution and subcellular function. As current imaging techniques are limited in spatial resolution, limiting insight into changes in calcium handling, computational models of excitation–contraction coupling have been increasingly employed to probe these structure–function relationships. This review will focus on the development of structural models of cardiac calcium dynamics at the subcellular level, orienting the reader broadly towards the development of models of subcellular calcium handling in cardiomyocytes. Specific focus will be given to progress in recent years in terms of multi-scale modeling employing resolved spatial models of subcellular calcium machinery. A review of the state-of-the-art will be followed by a review of emergent insights into calcium-dependent etiologies in heart disease and, finally, we will offer a perspective on future directions for related computational modeling and simulation efforts.

No MeSH data available.


Related in: MedlinePlus