Department of Pharmacology, University of California Davis, Davis, California.
Department of Pharmacology, University of California Davis, Davis, California.
Biophys J. 2019 Feb 5;116(3):530-539. doi: 10.1016/j.bpj.2018.12.017. Epub 2019 Jan 3.
Ryanodine receptors (RyRs) mediate calcium (Ca)-induced Ca release and intracellular Ca homeostasis. In a cardiac myocyte, RyRs group into clusters of variable size from a few to several hundred RyRs, creating a spatially nonuniform intracellular distribution. It is unclear how heterogeneity of RyR cluster size alters spontaneous sarcoplasmic reticulum (SR) Ca releases (Ca sparks) and arrhythmogenic Ca waves. Here, we tested the impact of heterogeneous RyR cluster size on the initiation of Ca waves. Experimentally, we measured RyR cluster sizes at Ca spark sites in rat ventricular myocytes and further tested functional impacts using a physiologically detailed computational model with spatial and stochastic intracellular Ca dynamics. We found that the spark frequency and amplitude increase nonlinearly with the size of RyR clusters. Larger RyR clusters have lower SR Ca release threshold for local Ca spark initiation and exhibit steeper SR Ca release versus SR Ca load relationship. However, larger RyR clusters tend to lower SR Ca load because of the higher Ca leak rate. Conversely, smaller clusters have a higher threshold and a lower leak, which tends to increase SR Ca load. At the myocyte level, homogeneously large or small RyR clusters limit Ca waves (because of low load for large clusters but low excitability for small clusters). Mixtures of large and small RyR clusters potentiates Ca waves because the enhanced SR Ca load driven by smaller clusters enables Ca wave initiation and propagation from larger RyR clusters. Our study suggests that a spatially heterogeneous distribution of RyR cluster size under pathological conditions may potentiate Ca waves and thus afterdepolarizations and triggered arrhythmias.
兰尼碱受体（RyRs）介导钙（Ca）诱导的 Ca 释放和细胞内 Ca 稳态。在心肌细胞中，RyRs 形成大小不一的簇，从几个到几百个 RyRs 不等，形成空间不均匀的细胞内分布。RyR 簇大小的异质性如何改变自发性肌浆网（SR）Ca 释放（Ca 火花）和致心律失常性 Ca 波尚不清楚。在这里，我们测试了 RyR 簇大小异质性对 Ca 波起始的影响。实验中，我们测量了大鼠心室肌细胞中 Ca 火花部位的 RyR 簇大小，并使用具有空间和随机细胞内 Ca 动力学的生理详细计算模型进一步测试了功能影响。我们发现，火花频率和幅度随 RyR 簇大小的非线性增加而增加。较大的 RyR 簇具有较低的 SR Ca 释放阈值，用于局部 Ca 火花的起始，并且在 SR Ca 释放与 SR Ca 负载关系方面表现出更陡峭的关系。然而，较大的 RyR 簇由于 Ca 泄漏率较高而倾向于降低 SR Ca 负载。相反，较小的簇具有较高的阈值和较低的泄漏，这倾向于增加 SR Ca 负载。在心肌细胞水平上，均匀的大或小 RyR 簇限制 Ca 波（因为大簇的负载低，但小簇的兴奋性低）。大、小 RyR 簇的混合物增强了 Ca 波，因为较小簇驱动的增强的 SR Ca 负载使 Ca 波能够从较大的 RyR 簇起始并传播。我们的研究表明，病理条件下 RyR 簇大小的空间异质性分布可能增强 Ca 波，从而增强后除极和触发心律失常。
