Construction of calcium release sites in cardiac myocytes
Construction of calcium release sites in cardiac myocytes
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DOI：
10.3389/fphys.2012.00322
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Zahradnik, Ivan
中科院分区：
文献类型：
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作者：
Zahradnikova, Alexandra;Zahradnik, Ivan
钙火花的共聚焦记录所定义的心肌细胞中钙释放的局部特征意味着基于兰尼碱受体（RyR）通道募集的单个钙释放位点的独立激活。我们构建了虚拟钙释放位点（vCRS）的RyR通道分布在集群中的一个变量的数量组成，根据实验观察到的集群大小分布。vCRS由单个虚拟钙释放单元（vCRU）组成，其中所有簇共享共同的二元空间，或者由多个虚拟钙释放单元（CRU）组成，每个虚拟钙释放单元包含一个簇并且具有单独的二元空间。我们探索了vCRS的随机行为，以了解钙火花期间RyR的激活和募集。RyR由已发表的变构门控模型表示，该模型包括细胞溶质Ca 2+和Mg 2+的调节。Mg 2+与RyR Ca 2+结合位点的相互作用和vCRS的不应期被优化以雅阁实验观察到的钙火花频率的钙依赖性。提供火花频率的最佳描述的RyR的Mg 2+结合参数取决于在vCRS中组装的RyR的数量。如果vCRS包含至少三个簇，则Mg 2+对RyR开放概率的钙依赖性具有足够的抑制作用。为了使诱发钙火花中开放RyR的数量分布与实验观察到的火花钙释放通量分布相对应，至少有三个簇必须共享一个共同的虚拟CRU，其中类似于3个RyR开放以形成平均火花。这些结果调和的小集群大小和随机放置的RyR在释放网站的RyR蛋白的量，钙释放网站的体积密度，和大鼠心肌细胞中的钙释放网站的大小的估计。
Local character of calcium release in cardiac myocytes, as defined by confocal recordings of calcium sparks, implies independent activation of individual calcium release sites based on ryanodine receptor (RyR) channel recruitment. We constructed virtual calcium release sites (vCRSs) composed of a variable number of RyR channels distributed in clusters in accordance with the experimentally observed cluster size distribution. The vCRSs consisted either of a single virtual calcium release unit (vCRU), in which all clusters shared a common dyadic space, or of multiple virtual calcium release units (CRUs) containing one cluster each and having separate dyadic spaces. We explored the stochastic behavior of vCRSs to understand the activation and recruitment of RyRs during calcium sparks. RyRs were represented by the published allosteric gating model that included regulation by cytosolic Ca2+ and Mg2+. The interaction of Mg2+ with the RyR Ca2+-binding sites and the refractory period of vCRSs were optimized to accord with the experimentally observed calcium dependence of calcium spark frequency. The Mg2+-binding parameters of RyRs that provided the best description of spark frequency depended on the number of RyRs assembled in the vCRSs. Adequate inhibitory effect of Mg2+ on the calcium dependence of RyR open probability was achieved if the vCRSs contained at least three clusters. For the distribution of the number of open RyRs in evoked calcium sparks to correspond to the experimentally observed distribution of spark calcium release fluxes, at least three clusters had to share a common virtual CRU, in which similar to 3 RyRs open to form an average spark. These results reconcile the small cluster size and stochastic placement of RyRs in the release sites with the estimates of the amount of RyR protein, volume density of calcium release sites, and the size of calcium release sites in rat cardiac myocytes.