Fill Michael, Gillespie Dirk
Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL, USA.
Pflugers Arch. 2021 Mar;473(3):435-446. doi: 10.1007/s00424-021-02539-w. Epub 2021 Feb 20.
Leak of Ca out of the cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) during diastole is vital to regulate SR Ca levels. This leak can become deleterious when large spontaneous RyR-mediated Ca release events evoke proarrhythmic Ca waves that can lead to delayed after-depolarizations. Here, we model diastolic SR Ca leak at individual SR Ca release sites using computer simulations of RyR arrays like those in the dyadic cleft. The results show that RyR arrays size has a significant effect on SR Ca leak, with bigger arrays producing larger and more frequent Ca release events. Moreover, big RyR arrays are more susceptible to small changes in the levels of dyadic Ca buffers. Such changes in buffering shift Ca leak from small Ca release events (involving few open RyRs) to larger events (with many open RyRs). Moreover, by analyzing a large parameter space of possible buffering and SR Ca loads, we find further evidence for the hypothesis that SR Ca leak by RyR arrays can undergo a sudden phase transition.
在舒张期，钙离子通过兰尼碱受体（RyRs）从心肌肌浆网（SR）泄漏对于调节肌浆网钙离子水平至关重要。当大量由兰尼碱受体介导的自发性钙离子释放事件引发促心律失常的钙波，进而导致延迟后去极化时，这种泄漏可能会变得有害。在此，我们使用类似于二联体裂隙中兰尼碱受体阵列的计算机模拟，对单个肌浆网钙离子释放位点的舒张期肌浆网钙离子泄漏进行建模。结果表明，兰尼碱受体阵列大小对肌浆网钙离子泄漏有显著影响，较大的阵列会产生更大且更频繁的钙离子释放事件。此外，大型兰尼碱受体阵列更容易受到二联体钙缓冲水平微小变化的影响。这种缓冲变化将钙泄漏从小的钙离子释放事件（涉及少量开放的兰尼碱受体）转变为大的事件（有许多开放的兰尼碱受体）。此外，通过分析可能的缓冲和肌浆网钙离子负荷的大参数空间，我们发现了进一步的证据支持兰尼碱受体阵列引起的肌浆网钙离子泄漏会经历突然相变这一假说。
