Using independent open-to-closed transitions to simplify aggregated Markov models of ion channel gating kinetics
Using independent open-to-closed transitions to simplify aggregated Markov models of ion channel gating kinetics
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DOI：
10.1073/pnas.0409110102
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发表时间：
2005-05-03
影响因子：
11.1
通讯作者：
Pearson, JE
中科院分区：
文献类型：
--
作者：
Bruno, WJ;Yang, J;Pearson, JE
从单通道电流迹线推导合理的反应方案既耗时又困难。我们的目标是找到适合数据的最简单方案，但是有许多方法可以连接甚至少量的状态（bbb200万个方案，其中有四个开放状态和四个封闭状态）。许多方案做出了相同的预测。对模型空间的详尽搜索并不能解决将产生的许多等效方案。我们找到了一个能表示二元通道所有反应方案的标准形式。这种形式对于任何秩（独立开闭跃迁的数量）都具有最小的速率常数，这与其他规范形式（如建立良好的“不耦合”模式）不同。由于新形式的所有导间跃迁都是独立的，因此我们将其称为显导间秩（MIR）形式。在四个开放状态和四个封闭状态的情况下，有四个MIR形式方案，对应于排名1-4。对于许多文献中提出的特定离子通道模型，等效的MIR形式具有比不耦合形式少得多的链接。通过使用MIR形式，我们证明了所有具有给定数量的开放和封闭状态的1阶拓扑在稳态下做出相同的预测，从而缩小了简单模型的搜索空间。此外，我们还证明了对标准形式的拟合保持了详细的平衡。我们还提出了一种有效的分层算法，用于搜索与给定数据集一致的最简单的可能模型。
Deducing plausible reaction schemes from single-channel current traces is time-consuming and difficult. The goal is to find the simplest scheme that fits the data, but there are many ways to connect even a small number of states (>2 million schemes with four open and four closed states). Many schemes make identical predictions. An exhaustive search over model space does not address the many equivalent schemes that will result. We have found a canonical form that can express all reaction schemes for binary channels. This form has the minimal number of rate constants for any rank (number of independent open-closed transitions), unlike other canonical forms such as the well established "uncoupled" scheme. Because all of the inter-conductance transitions in the new form are independent, we refer to it as the manifest interconductance rank (MIR) form. in the case of four open and four closed states, there are four MIR form schemes, corresponding to ranks 1-4. For many models proposed in the literature for specific ion channels, the equivalent MIR form has dramatically fewer links than the uncoupled form. By using the MIR form we prove that all rank 1 topologies with a given number of open and closed states make identical predictions in steady state, thus narrowing the search space for simple models. Moreover, we prove that fitting to canonical form preserves detailed balance. We also propose an efficient hierarchical algorithm for searching for the simplest possible model consistent with a given data set.