Computational Neurobiology Lab, The Salk Institute of Biological Studies, La Jolla, California; Department of Chemistry and Biochemistry, The University of California San Diego, La Jolla, California.
Computational Neurobiology Lab, The Salk Institute of Biological Studies, La Jolla, California.
Biophys J. 2024 Nov 5;123(21):3812-3831. doi: 10.1016/j.bpj.2024.09.029. Epub 2024 Oct 5.
We present the first-ever, fully discrete, stochastic model of triggered cardiac Ca dynamics. Using anatomically accurate subcellular cardiac myocyte geometries, we simulate the molecular players involved in Ca handling using high-resolution stochastic and explicit-particle methods at the level of an individual cardiac dyadic junction. Integrating data from multiple experimental sources, the model not only replicates the findings of traditional in silico studies and complements in vitro experimental data but also reveals new insights into the molecular mechanisms driving cardiac dysfunction under stress and disease conditions. We improve upon older, nondiscrete models using the same realistic geometry by incorporating molecular mechanisms for spontaneous, as well as triggered calcium-induced calcium release (CICR). Action potentials are used to activate L-type calcium channels (LTCC), triggering CICR through ryanodine receptors (RyRs) on the surface of the sarcoplasmic reticulum. These improvements allow for the specific focus on the couplon: the structure-function relationship between LTCC and RyR. We investigate the electrophysical effects of normal and diseased action potentials on CICR and interrogate the effects of dyadic junction deformation through detubulation and orphaning of RyR. Our work demonstrates the importance of the electrophysical integrity of the calcium release unit on CICR fidelity, giving insights into the molecular basis of heart disease. Finally, we provide a unique, detailed, molecular view of the CICR process using advanced rendering techniques. This easy-to-use model comes complete with tutorials and the necessary software for use and analysis to maximize usability and reproducibility. Our work focuses on quantifying, qualifying, and visualizing the behavior of the molecular species that underlie the function and dysfunction of subcellular cardiomyocyte systems.
我们提出了首个完全离散的、随机的触发型心脏钙动力学模型。使用解剖学上精确的亚细胞心肌细胞几何形状，我们使用高分辨率的随机和显式粒子方法，在单个心脏二联体连接点的水平上模拟涉及钙处理的分子成分。该模型整合了来自多个实验来源的数据，不仅复制了传统计算机模拟研究的发现，并补充了体外实验数据，还揭示了在应激和疾病条件下驱动心脏功能障碍的分子机制的新见解。我们通过在相同的现实几何形状上加入自发触发和触发钙诱导钙释放（CICR）的分子机制，对旧的非离散模型进行了改进。动作电位用于激活 L 型钙通道（LTCC），通过肌浆网表面的兰尼碱受体（RyRs）触发 CICR。这些改进使得可以特别关注偶联物：即 LTCC 和 RyR 之间的结构-功能关系。我们研究了正常和患病动作电位对 CICR 的电生理影响，并通过 RyR 的去管化和孤儿化来探究二联体连接点变形的影响。我们的工作表明钙释放单元的电生理完整性对 CICR 保真度的重要性，深入了解了心脏病的分子基础。最后，我们使用先进的渲染技术提供了 CICR 过程的独特、详细的分子视图。这个易于使用的模型提供了教程和必要的软件，以最大限度地提高可用性和可重复性。我们的工作重点是量化、定性和可视化构成亚细胞心肌细胞系统功能和功能障碍的分子成分的行为。
