Termination of cardiac Ca2+ sparks: role of intra-SR [Ca2+], release flux, and intra-SR Ca2+ diffusion.
Termination of cardiac Ca2+ sparks: role of intra-SR [Ca2+], release flux, and intra-SR Ca2+ diffusion.
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DOI：
10.1161/circresaha.107.183236
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发表时间：
2008-10-10
影响因子：
20.1
通讯作者：
Blatter LA
中科院分区：
文献类型：
--
作者：
Zima AV;Picht E;Bers DM;Blatter LA
心肌肌浆网（SR）通过RyRs释放Ca ~（2+）受二进裂隙[Ca ~（2+）]和SR内游离[Ca ~（2+）]（[Ca ~（2+）SR）的调节。稳定的SR Ca 2+释放终止对于稳定的兴奋-收缩偶联是重要的，并且部分[Ca 2 +]SR耗尽可能有助于释放终止。在这里，我们研究了调节SR Ca 2+释放终止自发的局部SR Ca 2+释放事件（Ca 2+火花）的[Ca 2 +]SR，释放通量，和内SR Ca 2+扩散。我们同时测量了钙火花和钙闪烁（本地化的基本[Ca 2 +]SR耗尽）在透化的心室心肌细胞在广泛的SR Ca 2+负荷和释放通量。火花终止通过[Ca 2 +] SR依赖的机制在一个固定的[Ca 2 +]SR耗尽阈值独立的初始[Ca 2 +]SR和释放通量。Ca ~（2+）眨眼恢复主要依赖于SR内Ca ~（2+）扩散而不是SR内Ca ~（2+）摄取。因此，在不同的释放网站的Ca 2+闪烁恢复率的大的变化发生，因为在SR网络内的释放网站互连的程度的差异。当SR释放通量大大降低时，长时间的释放事件发生在连接良好的连接处。这些连接可以持续释放，因为局部SR Ca 2+释放和[Ca 2 +]SR再填充达到平衡，防止[Ca 2 +]SR耗尽到终止阈值。延长的释放事件最终终止于稳定的[Ca 2 +]SR，表明一个较慢的，[Ca 2 +] SR独立的终止机制。这些结果表明，有很高的变异性，在本地SR连接，但SR Ca 2+释放终止在一个固定的[Ca 2 +]SR终止阈值。因此，可靠的SR Ca 2+释放终止取决于[Ca 2 +] SR对RyR的严格调节。
Ca2+ release from cardiac sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) is regulated by dyadic cleft [Ca2+] and intra-SR free [Ca2+] ([Ca2+]SR). Robust SR Ca2+ release termination is important for stable excitation–contraction coupling, and partial [Ca2+]SR depletion may contribute to release termination. Here, we investigated the regulation of SR Ca2+ release termination of spontaneous local SR Ca2+ release events (Ca2+ sparks) by [Ca2+]SR, release flux, and intra-SR Ca2+ diffusion. We simultaneously measured Ca2+ sparks and Ca2+ blinks (localized elementary [Ca2+]SR depletions) in permeabilized ventricular cardiomyocytes over a wide range of SR Ca2+ loads and release fluxes. Sparks terminated via a [Ca2+]SR-dependent mechanism at a fixed [Ca2+]SR depletion threshold independent of the initial [Ca2+]SR and release flux. Ca2+ blink recovery depended mainly on intra-SR Ca2+ diffusion rather than SR Ca2+ uptake. Therefore, the large variation in Ca2+ blink recovery rates at different release sites occurred because of differences in the degree of release site interconnection within the SR network. When SR release flux was greatly reduced, long-lasting release events occurred from well-connected junctions. These junctions could sustain release because local SR Ca2+ release and [Ca2+]SR refilling reached a balance, preventing [Ca2+]SR from depleting to the termination threshold. Prolonged release events eventually terminated at a steady [Ca2+]SR, indicative of a slower, [Ca2+]SR-independent termination mechanism. These results demonstrate that there is high variability in local SR connectivity but that SR Ca2+ release terminates at a fixed [Ca2+]SR termination threshold. Thus, reliable SR Ca2+ release termination depends on tight RyR regulation by [Ca2+]SR.