Local control models of cardiac excitation-contraction coupling. A possible role for allosteric interactions between ryanodine receptors.
Local control models of cardiac excitation-contraction coupling. A possible role for allosteric interactions between ryanodine receptors.
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DOI：
10.1085/jgp.113.3.469
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发表时间：
1999-03
期刊：
影响因子：
--
通讯作者：
Ríos E
中科院分区：
文献类型：
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作者：
Stern MD;Song LS;Cheng H;Sham JS;Yang HT;Boheler KR;Ríos E
在心肌中，激活剂钙从肌浆网的释放通过钙诱导的钙释放通过兰尼碱受体（RyR）发生，所述RyR在二联体连接处聚集成密集的、规则的二维晶格阵列。我们数值模拟了RyRs和L-型肌膜钙通道通过连接裂隙中的钙纳米结构域相互作用的随机动力学。四个假定的RyR门控计划的基础上单通道测量脂质双层都未能得到稳定的兴奋-收缩耦合，由于不够强的失活终止局部再生钙诱导的钙释放或不足的协同性，以歧视RyR激活背景钙。如果兰尼碱受体的代表，而不是一个现象学的四态门控方案，与通道开放导致同时结合的两个钙离子，无论是钙依赖性或激活相关的失活，模拟给出了一个很好的半定量占宏观特征的兴奋-收缩耦合。这是可能的恢复稳定的模型的基础上的双层衍生的门控方案，通过引入最近的邻居RyR之间的变构相互作用，以稳定失活状态，并产生不同RyR上的钙结合位点之间的协同性。RyRs之间的这种变构耦合可能是足突和晶格阵列的函数，解释了它们在进化过程中的保守性。
In cardiac muscle, release of activator calcium from the sarcoplasmic reticulum occurs by calcium- induced calcium release through ryanodine receptors (RyRs), which are clustered in a dense, regular, two-dimensional lattice array at the diad junction. We simulated numerically the stochastic dynamics of RyRs and L-type sarcolemmal calcium channels interacting via calcium nano-domains in the junctional cleft. Four putative RyR gating schemes based on single-channel measurements in lipid bilayers all failed to give stable excitation–contraction coupling, due either to insufficiently strong inactivation to terminate locally regenerative calcium-induced calcium release or insufficient cooperativity to discriminate against RyR activation by background calcium. If the ryanodine receptor was represented, instead, by a phenomenological four-state gating scheme, with channel opening resulting from simultaneous binding of two Ca2+ ions, and either calcium-dependent or activation-linked inactivation, the simulations gave a good semiquantitative accounting for the macroscopic features of excitation–contraction coupling. It was possible to restore stability to a model based on a bilayer-derived gating scheme, by introducing allosteric interactions between nearest-neighbor RyRs so as to stabilize the inactivated state and produce cooperativity among calcium binding sites on different RyRs. Such allosteric coupling between RyRs may be a function of the foot process and lattice array, explaining their conservation during evolution.