Zoghbi M E, Copello J A, Villalba-Galea C A, Vélez P, Diaz Sylvester P L, Bolaños P, Marcano A, Fill M, Escobar A L
Centro de Biofisica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
Cell Calcium. 2004 Aug;36(2):119-34. doi: 10.1016/j.ceca.2004.01.023.
The regulation of the Ca2+ -induced Ca2+ release (CICR) from intracellular stores is a critical step in the cardiac cycle. The inherent positive feedback of CICR should make it a self-regenerating process. It is accepted that CICR must be governed by some negative control, but its nature is still debated. We explore here the importance of the Ca2+ released from sarcoplasmic reticulum (SR) on the mechanisms that may control CICR. Specifically, we compared the effect of replacing Ca2+ with Sr2+ on intracellular Ca2+ signaling in intact cardiac myocytes as well as on the function of single ryanodine receptor (RyR) Ca2+ release channels in panar bilayers. In cells, both CICR and Sr2+ -induced Sr2+ release (SISR) were observed. Action potential induced Ca2+ -transients and spontaneous Ca2+ waves were considerably faster than their Sr2+ -mediated counterparts. However, the kinetics of Ca2+ and Sr2+ sparks was similar. At the single RyR channel level, the affinities of Ca2+ and Sr2+ activation were different but the affinities of Ca2+ and Sr2+ inactivation were similar. Fast Ca2+ and Sr2+ stimuli activated RyR channels equally fast but adaptation (a spontaneous slow transition back to steady-state activity levels) was not observed in the Sr2+ case. Together, these results suggest that regulation of the RyR channel by cytosolic Ca2+ is not involved in turning off the Ca2+ spark. In contrast, cytosolic Ca2+ is important in the propagation global Ca2+ release events and in this regard single RyR channel sensitivity to cytosolic Ca2+ activation, not low-affinity cytosolic Ca2+ inactivation, is a key factor. This suggests that the kinetics of local and global RyR-mediated Ca2+ release signals are affected in a distinct way by different divalent cations in cardiac muscle cells.
细胞内钙库中钙诱导的钙释放（CICR）调节是心动周期中的关键步骤。CICR固有的正反馈应使其成为一个自我再生过程。人们普遍认为CICR必须受某种负调控，但调控的本质仍存在争议。我们在此探讨肌浆网（SR）释放的Ca²⁺对可能控制CICR的机制的重要性。具体而言，我们比较了用Sr²⁺替代Ca²⁺对完整心肌细胞内Ca²⁺信号传导以及平面双层中单个兰尼碱受体（RyR）Ca²⁺释放通道功能的影响。在细胞中，观察到了CICR和Sr²⁺诱导的Sr²⁺释放（SISR）。动作电位诱导的Ca²⁺瞬变和自发Ca²⁺波比它们的Sr²⁺介导的对应物快得多。然而，Ca²⁺和Sr²⁺闪烁的动力学相似。在单个RyR通道水平，Ca²⁺和Sr²⁺激活的亲和力不同，但Ca²⁺和Sr²⁺失活的亲和力相似。快速的Ca²⁺和Sr²⁺刺激以相同的速度激活RyR通道，但在Sr²⁺的情况下未观察到适应性变化（自发缓慢转变回稳态活性水平）。总之，这些结果表明，胞质Ca²⁺对RyR通道的调节不参与关闭Ca²⁺闪烁。相反，胞质Ca²⁺在全局Ca²⁺释放事件的传播中很重要，在这方面，单个RyR通道对胞质Ca²⁺激活的敏感性而非低亲和力的胞质Ca²⁺失活是关键因素。这表明，心肌细胞中不同二价阳离子以不同方式影响局部和全局RyR介导的Ca²⁺释放信号的动力学。
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