Department of Biomedical Engineering, Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, Missouri, USA.
Biophys J. 2011 Jun 22;100(12):2904-12. doi: 10.1016/j.bpj.2011.05.031.
In cardiac ventricular myocytes, calcium (Ca) release occurs at distinct structures (dyads) along t-tubules, where L-type Ca channels (LCCs) appose sarcoplasmic reticulum (SR) Ca release channels (RyR2s). We developed a model of the cardiac ventricular myocyte that simulates local stochastic Ca release processes. At the local Ca release level, the model reproduces Ca spark properties. At the whole-cell level, the model reproduces the action potential, Ca currents, and Ca transients. Changes in microscopic dyadic properties (e.g., during detubulation in heart failure) affect whole-cell behavior in complex ways, which we investigated by simulating changes in the dyadic volume and number of LCCs/RyR2s in the dyad, and effects of calsequestrin (CSQN) as a Ca buffer (CSQN buffer) or a luminal Ca sensor (CSQN regulator). We obtained the following results: 1), Increased dyadic volume and reduced LCCs/RyR2s decrease excitation-contraction coupling gain and cause asynchrony of SR Ca release, and interdyad coupling partially compensates for the reduced synchrony. 2), Impaired CSQN buffer depresses Ca transients without affecting the synchrony of SR Ca release. 3), When CSQN regulator function is impaired, interdyad coupling augments diastolic Ca release activity to form Ca waves and long-lasting Ca release events.
在心肌细胞中，钙离子（Ca）释放发生在 T 管上的特定结构（对偶结构）处，其中 L 型钙通道（LCC）与肌质网（SR）Ca 释放通道（RyR2）相对。我们开发了一种模拟心肌细胞局部随机 Ca 释放过程的模型。在局部 Ca 释放水平上，该模型再现了 Ca 火花特性。在整个细胞水平上，该模型再现了动作电位、Ca 电流和 Ca 瞬变。微观对偶结构的变化（例如，心力衰竭时的脱管）以复杂的方式影响整个细胞的行为，我们通过模拟对偶结构中 LCC/RyR2 的对偶体积和数量的变化以及 calsequestrin（CSQN）作为 Ca 缓冲剂（CSQN 缓冲剂）或腔 Ca 传感器（CSQN 调节剂）的作用来研究这些变化。我们得到了以下结果：1），增加对偶体积和减少 LCC/RyR2 降低兴奋-收缩偶联增益并导致 SR Ca 释放的不同步，并且偶联部分补偿了同步性的降低。2），受损的 CSQN 缓冲剂会降低 Ca 瞬变而不影响 SR Ca 释放的同步性。3），当 CSQN 调节剂功能受损时，偶联会增强舒张期 Ca 释放活性，形成 Ca 波和长时间的 Ca 释放事件。
