Calcium regulation of single ryanodine receptor channel gating analyzed using HMM/MCMC statistical methods.
Calcium regulation of single ryanodine receptor channel gating analyzed using HMM/MCMC statistical methods.
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DOI：
10.1085/jgp.200308868
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发表时间：
2004-05
影响因子：
3.8
通讯作者：
Escobar, Ariel L
中科院分区：
文献类型：
--
作者：
Rosales, Rafael A;Fill, Michael;Escobar, Ariel L
ii型ryanodine受体通道（RYRs）在心脏细胞内Ca2+动力学中起着重要作用。这些通道的激活、失活和调节过程一直是深入研究的主题，也是最近争论的焦点。通常，理解这些过程的方法包括对单个ryr的统计分析，包括信号恢复、模型估计和选择。这些任务通常通过遵循相当现象学的标准来执行，这些标准将模型转变为自我实现的预言。在这里，通过使用聚合隐马尔可夫模型对单个ryr进行建模，应用了彻底的统计处理。推理使用贝叶斯统计和随机搜索方法，即马尔可夫链蒙特卡罗。这些方法允许扩展分析的时间分辨率，远远超出先前方法的限制，并提供与每个估计步骤相关的不确定性的直接度量，以及对特定模型失败的原因和位置的直接评估。通过考虑16种模型，对几种Ca2+浓度下的单个ryr进行了分析，其中一些模型先前在文献中报道过。结果清楚地表明，单个ryr具有Ca2+依赖的门控模式。此外，我们的研究结果表明，单个ryr响应Ca2+的突然变化显示适应动力学。有趣的是，当一价阳离子作为主要的渗透物种时，排名最好的模型预测微观可逆性。最后，扩展的带宽揭示了在低Ca2+浓度下存在新的快速蜂鸣声模式。
Type-II ryanodine receptor channels (RYRs) play a fundamental role in intracellular Ca2+ dynamics in heart. The processes of activation, inactivation, and regulation of these channels have been the subject of intensive research and the focus of recent debates. Typically, approaches to understand these processes involve statistical analysis of single RYRs, involving signal restoration, model estimation, and selection. These tasks are usually performed by following rather phenomenological criteria that turn models into self-fulfilling prophecies. Here, a thorough statistical treatment is applied by modeling single RYRs using aggregated hidden Markov models. Inferences are made using Bayesian statistics and stochastic search methods known as Markov chain Monte Carlo. These methods allow extension of the temporal resolution of the analysis far beyond the limits of previous approaches and provide a direct measure of the uncertainties associated with every estimation step, together with a direct assessment of why and where a particular model fails. Analyses of single RYRs at several Ca2+ concentrations are made by considering 16 models, some of them previously reported in the literature. Results clearly show that single RYRs have Ca2+-dependent gating modes. Moreover, our results demonstrate that single RYRs responding to a sudden change in Ca2+ display adaptation kinetics. Interestingly, best ranked models predict microscopic reversibility when monovalent cations are used as the main permeating species. Finally, the extended bandwidth revealed the existence of novel fast buzz-mode at low Ca2+ concentrations.