Mechanisms of excitation-contraction coupling in an integrative model of the cardiac ventricular myocyte
Mechanisms of excitation-contraction coupling in an integrative model of the cardiac ventricular myocyte
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DOI：
10.1529/biophysj.105.065169
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发表时间：
2006-01-01
影响因子：
3.4
通讯作者：
Winslow, RL
中科院分区：
文献类型：
--
作者：
Greenstein, JL;Hinch, R;Winslow, RL
现在已经确定，心肌细胞中兴奋-收缩（EC）偶联的特征性质，例如高增益和分级的Ca 2+释放，是由局部微区中L型Ca 2+通道（LCC）和附近的ryanodine敏感性Ca 2+释放通道（RyR）之间发生的相互作用引起的。解释这些局部机制的Ca 2+诱导的Ca 2+释放（CICR）的描述缺乏来自心脏动作电位的许多先前模型，并且那些确实包括CICR的局部控制的模型能够重建EC耦合的性质，但是需要计算上苛刻的类似于10（5）个单独离子通道的随机模拟。在这项研究中，我们概括了最近开发的分析方法，用于推导简化的CICR机制模型，制定一个综合模型的犬心肌细胞，这是计算效率。很好。由此产生的模型忠实地再现实验测得的EC耦合和全细胞现象的属性。该模型被用来研究局部冗余在L-型Ca ~（2+）通道门控中的作用和二元结构在EC耦合中的作用。模拟表明，EC耦合增益的特征急剧上升，观察到在超极化电位是LCC和RyRs之间的功能耦合增加的结果。我们还证明了在早期复极化阶段的动作电位，减少瞬态外向钾电流，改变EC耦合的性质所造成的改变的机制。
It is now well established that characteristic properties of excitation- contraction (EC) coupling in cardiac myocytes, such as high gain and graded Ca2+ release, arise from the interactions that occur between L-type Ca2+ channels (LCCs) and nearby ryanodine-sensitive Ca2+ release channels (RyRs) in localized microdomains. Descriptions of Ca2+-induced Ca2+ release (CICR) that account for these local mechanisms are lacking from many previous models of the cardiac action potential, and those that do include local control of CICR are able to reconstruct properties of EC coupling, but require computationally demanding stochastic simulations of similar to 10(5) individual ion channels. In this study, we generalize a recently developed analytical approach for deriving simplified mechanistic models of CICR to formulate an integrative model of the canine cardiac myocyte which is computationally effi. cient. The resulting model faithfully reproduces experimentally measured properties of EC coupling and whole cell phenomena. The model is used to study the role of local redundancy in L-type Ca2+ channel gating and the role of dyad configuration on EC coupling. Simulations suggest that the characteristic steep rise in EC coupling gain observed at hyperpolarized potentials is a result of increased functional coupling between LCCs and RyRs. We also demonstrate mechanisms by which alterations in the early repolarization phase of the action potential, resulting from reduction of the transient outward potassium current, alters properties of EC coupling.