Thermodynamically irreversible gating of ryanodine receptors in situ revealed by stereotyped duration of release in Ca2+ sparks
Thermodynamically irreversible gating of ryanodine receptors in situ revealed by stereotyped duration of release in Ca2+ sparks
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DOI：
10.1016/s0006-3495(02)75165-5
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发表时间：
2002-07-01
影响因子：
3.4
通讯作者：
Cheng, H
中科院分区：
文献类型：
--
作者：
Wang, SQ;Song, LS;Cheng, H
对于单个或一组可逆马尔可夫通道，打开和关闭时间的分布应该是正加权衰减指数之和。先前已经在单通道水平上多次证明了这种微观可逆性的破坏，并且归因于可能的通道与外部自由能源的耦合。在这里，我们表明，完整心肌细胞中 Ca2+ 放电潜在的 Ca2+ 释放持续时间的分布表现出类似于 8 ms 的显着模式。对过度活跃部位重复火花的周期时间的分析显示，没有任何间隔比大约 35 毫秒更短，并且模式大约为 90 毫秒。这些结果表明，无论Ca2+火花的起源是单通道还是多通道，它们都是由热力学不可逆随机过程产生的。相比之下，平面脂质双层实验的数据与不对称顺式（4μM）和反式Ca2+（10mM）下RyR的可逆门控一致，表明Ca2+火花发生的不可逆性可能存在于超分子水平。建模表明，相邻 RyR 之间 Ca2+ 诱导的 Ca2+ 释放可能会将来自 SR 上 Ca2+ 梯度的外部能量耦合到原位 RyR 门控，并驱动 Ca2+ 火花的不可逆生成。
For a single or a group of Markov channels gating reversibly, distributions of open and closed times should be the sum of positively weighted decaying exponentials. Violation of this microscopic reversibility has been demonstrated previously on a number of occasions at the single channel level, and has been attributed to possible channel coupling to external sources of free energy. Here we show that distribution of durations of Ca2+ release underlying Ca2+ sparks in intact cardiac myocytes exhibits a prominent mode at similar to8 ms. Analysis of the cycle time for repetitive sparks at hyperactive sites revealed no intervals briefer than similar to35 ms and a mode at similar to90 ms. These results indicate that, regardless of whether Ca2+ sparks are single-channel or multi-channel in origin, they are generated by thermodynamically irreversible stochastic processes. In contrast, data from planar lipid bilayer experiments were consistent with reversible gating of RyR under asymmetric cis (4 muM) and trans Ca2+ (10 mM), Suggesting that the irreversibility for Ca2+ spark genesis may reside at a supramolecular level. Modeling suggests that Ca2+-induced Ca2+ release among adjacent RyRs may couple the external energy derived from Ca2+ gradients across the SR to RyR gating in situ, and drive the irreversible generation of Ca2+ sparks.