Sato Daisuke, Ghayoumi Bardia, Fasoli Anna, Ko Christopher Y, Bers Donald M
Department of Pharmacology, University of California, Davis, Davis, California.
Department of Pharmacology, University of California, Davis, Davis, California.
Biophys J. 2025 Mar 4;124(5):717-721. doi: 10.1016/j.bpj.2025.01.023. Epub 2025 Jan 31.
Structural heterogeneity in the distribution of ryanodine receptor (RyR) clusters in cardiac myocytes has been shown to have pro-arrhythmic effects. The presence of a mixture of large and small RyR clusters can potentiate arrhythmogenic calcium (Ca) waves. RyRs are subject to posttranslational modifications (PTMs), such as phosphorylation, that are linked to heart failure and other pathological conditions. This study aims to investigate how PTMs interact with the structural heterogeneity of RyR clusters and further increase heterogeneous Ca release activities in cardiac myocytes. Using a physiologically detailed three-dimensional ventricular myocyte model containing approximately 2 million stochastic RyR channels, we simulated heterogeneous distributions of RyR clusters with and without PTMs. The results demonstrate that Ca cycling and RyR phosphorylation by Ca/calmodulin-dependent protein kinase II (CaMKII) create a positive feedback loop, which increases functional heterogeneity in the Ca spark size distribution. In large clusters, the Ca leak is substantial due to the large flux (number of channels recruited), leading to increased local Ca concentrations, CaMKII activation, and further RyR sensitization, amplifying the leak. Conversely, in small clusters, the leak is limited, and sensitization is restricted. Furthermore, CaMKII activation can enhance late sodium (Na) currents, increasing Na influx and subsequently raising Ca levels via the Na-Ca exchanger, further promoting the Ca leak and functional heterogeneity. We conclude that such positive feedback processes play a crucial role in arrhythmogenic Ca wave initiation and propagation, particularly in heart failure myocytes, where PTMs are often dysregulated.
心肌细胞中兰尼碱受体（RyR）簇分布的结构异质性已被证明具有促心律失常作用。大小不同的RyR簇混合存在会增强致心律失常的钙（Ca）波。RyR会发生翻译后修饰（PTM），如磷酸化，这与心力衰竭和其他病理状况有关。本研究旨在探讨PTM如何与RyR簇的结构异质性相互作用，并进一步增加心肌细胞中异质性钙释放活性。我们使用一个包含约200万个随机RyR通道的生理细节三维心室肌细胞模型，模拟了有无PTM时RyR簇的异质分布。结果表明，Ca循环以及Ca/钙调蛋白依赖性蛋白激酶II（CaMKII）介导的RyR磷酸化形成了一个正反馈回路，这增加了钙火花大小分布的功能异质性。在大簇中，由于通量较大（募集的通道数量），Ca泄漏相当可观，导致局部Ca浓度升高、CaMKII激活以及进一步的RyR敏化，从而放大了泄漏。相反，在小簇中，泄漏有限，敏化也受到限制。此外，CaMKII激活可增强晚钠（Na）电流，增加Na内流，随后通过钠钙交换体提高Ca水平，进一步促进Ca泄漏和功能异质性。我们得出结论，这种正反馈过程在致心律失常性钙波的起始和传播中起着关键作用，尤其是在心力衰竭心肌细胞中，其中PTM常常失调。
