Ryanodine receptor allosteric coupling and the dynamics of calcium sparks
Ryanodine receptor allosteric coupling and the dynamics of calcium sparks
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DOI：
10.1529/biophysj.107.119982
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发表时间：
2008-07-01
影响因子：
3.4
通讯作者：
Smith, Gregory D.
中科院分区：
文献类型：
--
作者：
Groff, Jeffrey R.;Smith, Gregory D.
泡和火花是局部的细胞内Ca2+升高，由Ca2+调节的肌醇1,4,5-三磷酸受体和ryanodine受体聚集在内质网或肌浆网表面的Ca2+释放位点的协同活动引起。虽然Ca2+调控的Ca2+通道的同步门控可以完全通过细胞内Ca2+的缓冲扩散介导，但蛋白间变构相互作用也有助于ryanodine受体（RyR）门控和Ca2+火花的动力学。在本文中，使用Ca2+释放位点的马尔可夫链模型来研究Ca2+火花产生和终止的统计数据如何与RyRs通过局部[Ca2+]变化和变构相互作用的耦合相关。变构相互作用通过稳定相邻的封闭和/或开放通道对来促进通道的同步门控。当Ca2+介导的通道耦合的强度是系统地变化（例如，通过改变Ca2+缓冲浓度），模拟包括同步变构相互作用往往表现出更强大的Ca2+火花；然而，对于某些Ca2+偶联强度，火花不太坚固。我们发现没有证据表明火花持续时间的分布可以用来区分变构相互作用，以平衡的方式稳定封闭通道对，开放通道对或两者。另一方面，当稳定封闭通道对的变构相互作用逐渐从模拟中移除时，观察到的火花持续时间、火花间隔和频率的变化与稳定开放通道对或同时稳定封闭和开放通道对时观察到的变化有质的不同。因此，我们的模拟阐明了由于介导变构耦合的辅助蛋白的药理学清洗而导致的火花统计变化如何表明物理偶联的ryr所表现出的同步变构相互作用的类型。我们还研究了适用于通过局部[Ca2+]和变构相互作用耦合的ryanodine受体簇动力学的平均场还原的有效性。除了促进变构耦合对火花统计影响的参数研究外，平均场模型的推导建立了代表ryr耦合门控的协同性因子的正确函数形式。这种平均场公式非常适合用于计算效率高的激发-收缩耦合的全细胞模拟。
Puffs and sparks are localized intracellular Ca2+ elevations that arise from the cooperative activity of Ca2+-regulated inositol 1,4,5-trisphosphate receptors and ryanodine receptors clustered at Ca2+ release sites on the surface of the endoplasmic reticulum or the sarcoplasmic reticulum. While the synchronous gating of Ca2+-regulated Ca2+ channels can be mediated entirely though the buffered diffusion of intracellular Ca2+, interprotein allosteric interactions also contribute to the dynamics of ryanodine receptor (RyR) gating and Ca2+ sparks. In this article, Markov chain models of Ca2+ release sites are used to investigate how the statistics of Ca2+ spark generation and termination are related to the coupling of RyRs via local [Ca2+] changes and allosteric interactions. Allosteric interactions are included in a manner that promotes the synchronous gating of channels by stabilizing neighboring closed-closed and/or open-open channel pairs. When the strength of Ca2+-mediated channel coupling is systematically varied (e.g., by changing the Ca2+ buffer concentration), simulations that include synchronizing allosteric interactions often exhibit more robust Ca2+ sparks; however, for some Ca2+ coupling strengths the sparks are less robust. We find no evidence that the distribution of spark durations can be used to distinguish between allosteric interactions that stabilize closed channel pairs, open channel pairs, or both in a balanced fashion. On the other hand, the changes in spark duration, interspark interval, and frequency observed when allosteric interactions that stabilize closed channel pairs are gradually removed from simulations are qualitatively different than the changes observed when open or both closed and open channel pairs are stabilized. Thus, our simulations clarify how changes in spark statistics due to pharmacological washout of the accessory proteins mediating allosteric coupling may indicate the type of synchronizing allosteric interactions exhibited by physically coupled RyRs. We also investigate the validity of a mean-field reduction applicable to the dynamics of a ryanodine receptor cluster coupled via local [Ca2+] and allosteric interactions. In addition to facilitating parameter studies of the effect of allosteric coupling on spark statistics, the derivation of the mean-field model establishes the correct functional form for cooperativity factors representing the coupled gating of RyRs. This mean-field formulation is well suited for use in computationally efficient whole cell simulations of excitation-contraction coupling.