Nanoscale organization of ryanodine receptor distribution and phosphorylation pattern determines the dynamics of calcium sparks

Mesa, María Hernández; Brink, Jonas van den; Louch, William E.; McCabe, Kimberly J.; Rangamani, Padmini

doi:10.1016/j.bpj.2021.11.865

Cited by 2 publications

(2 citation statements)

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“…This model also included differentiation between non-phosphorylated and phosphorylated RyRs (modeled as a simple increase in sensitivity to Ca 2+ ), and results support the conclusions of both Cannell et al (2013) and Walker et al (2014) regarding the importance of both number and specific arrangement of RyRs for triggered Ca 2+ spark dynamics and fidelity. Mesa et al (2021) also investigated the functional impact of selected phosphorylated RyRs within a cluster, indicating that they can play a compensatory role in recovering healthy spark dynamics which had been lost through cluster disruption. Iaparov et al (2021) developed a 2D model which included further possibilities for RyR arrangement and spacing (including both approaches outlined above), number, and dyad extent.…”

Section: Spatial Models Of the Single Dyad/nanodomainmentioning

confidence: 99%

“…The most straight-forward method is to implement the Monte-Carlo approach: the state of each individual channel is tracked directly, and state-transitions are determined based on random numbers and the probability of transition The release flux is then given by the sum of the open channels in each dyad. This approach is ideally suited to cases where each individual channel is required to be tracked, for example in spatial models of the single nanodomain (Mesa et al, 2021). However, in larger models, e.g., of the wholecell, this then requires the state of ∼50 RyRs + ∼15 LTCCs per dyad × ∼20,000 dyads to be tracked individually, with random numbers generated to determine state transitions for each one, which can be computationally intensive.…”

Section: Numerical Solutions To the Ryanodine Receptors Modelmentioning

confidence: 99%

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Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives

et al. 2022

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Regulation of intracellular calcium is a critical component of cardiac electrophysiology and excitation-contraction coupling. The calcium spark, the fundamental element of the intracellular calcium transient, is initiated in specialized nanodomains which co-locate the ryanodine receptors and L-type calcium channels. However, calcium homeostasis is ultimately regulated at the cellular scale, by the interaction of spatially separated but diffusively coupled nanodomains with other sub-cellular and surface-membrane calcium transport channels with strong non-linear interactions; and cardiac electrophysiology and arrhythmia mechanisms are ultimately tissue-scale phenomena, regulated by the interaction of a heterogeneous population of coupled myocytes. Recent advances in imaging modalities and image-analysis are enabling the super-resolution reconstruction of the structures responsible for regulating calcium homeostasis, including the internal structure of nanodomains themselves. Extrapolating functional and imaging data from the nanodomain to the whole-heart is non-trivial, yet essential for translational insight into disease mechanisms. Computational modeling has important roles to play in relating structural and functional data at the sub-cellular scale and translating data across the scales. This review covers recent methodological advances that enable image-based modeling of the single nanodomain and whole cardiomyocyte, as well as the development of multi-scale simulation approaches to integrate data from nanometer to whole-heart. Firstly, methods to overcome the computational challenges of simulating spatial calcium dynamics in the nanodomain are discussed, including image-based modeling at this scale. Then, recent whole-cell models, capable of capturing a range of different structures (such as the T-system and mitochondria) and cellular heterogeneity/variability are discussed at two different levels of discretization. Novel methods to integrate the models and data across the scales and simulate stochastic dynamics in tissue-scale models are then discussed, enabling elucidation of the mechanisms by which nanodomain remodeling underlies arrhythmia and contractile dysfunction. Perspectives on model differences and future directions are provided throughout.

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