On the Adjacency Matrix of RyR2 Cluster Structures.
On the Adjacency Matrix of RyR2 Cluster Structures.
复制标题
在RYR2群集结构的邻接矩阵上。
DOI：
10.1371/journal.pcbi.1004521
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发表时间：
2015-11
影响因子：
4.3
通讯作者：
Winslow RL
中科院分区：
文献类型：
--
作者：
Walker MA;Kohl T;Lehnart SE;Greenstein JL;Lederer WJ;Winslow RL
在心脏中，对心肌细胞的电刺激增加了肌膜电压敏感的钙通道的开放概率和钙离子进入细胞的流量。这增加了钙离子与被称为兰尼定受体(RyR2)的配体门控通道的结合。它们的开口导致全细胞范围的钙离子释放，进而导致肌肉收缩和产生泵血所需的机械力。在静息的心肌细胞中，RyR2也可以自发开放，引起空间受限的钙释放事件，称为“火花”。RyR2以晶格形式排列，在连接的肌质网膜上形成簇。我们最近的工作表明，RyR2在团簇中的空间排列强烈地影响着钙离子火花的频率。我们发现，当星系团中的单个RyR2自发开启时，发生钙离子火花的概率可以从RyR2的精确空间排列中预测出来。因此，“功能”紧随“结构”之后。这个概率与RyR2团簇晶格的邻接矩阵的最大本征值(λ1)有关。在这项工作中，我们开发了一个理论框架来理解这种关系。我们提出了一个钙离子火花引发过程的随机接触网络模型。我们表明，λ1根据RyR2门控跃迁速率确定了钙火花形成的稳定阈值。我们通过将该模型应用于超分辨受激辐射耗尽(STED)显微镜获得的真实RyR2团簇结构，概括了这些结果。线性化平均场接触网络模型的特征分解揭示了RyR2团簇中的功能亚域对钙离子具有不同的敏感性。这项工作为心脏钙释放过程提供了新的视角，并为从结构推断跨膜受体簇的功能特性提供了一种通用的方法。许多跨膜受体已被证明聚集成超分子簇，在各种类型的细胞中增强对外部刺激的敏感性。超分辨率显微镜的进步使研究人员能够以足够的细节研究这些结构，以区分单个受体的准确位置。在心脏方面，已经成功地对钙释放通道进行了成像，在心肌细胞的肌浆网膜中发现了高达∼100的簇状钙释放通道。我们在最近的一项研究中展示了精确的星团结构是如何影响被称为钙“火花”的自发释放事件的频率的。在这里，我们开发了一个钙火花引发的分析模型，清楚地说明了该结构如何控制火花可能性。然后，我们将该模型应用于使用超分辨率显微镜获得的一组通道簇结构，揭示了单个通道功能属性的空间梯度。这项工作提供了对心脏中钙释放过程的洞察，并为仅使用结构信息评估受体簇群体的功能异质性提供了一个框架。
In the heart, electrical stimulation of cardiac myocytes increases the open probability of sarcolemmal voltage-sensitive Ca2+ channels and flux of Ca2+ into the cells. This increases Ca2+ binding to ligand-gated channels known as ryanodine receptors (RyR2). Their openings cause cell-wide release of Ca2+, which in turn causes muscle contraction and the generation of the mechanical force required to pump blood. In resting myocytes, RyR2s can also open spontaneously giving rise to spatially-confined Ca2+ release events known as “sparks.” RyR2s are organized in a lattice to form clusters in the junctional sarcoplasmic reticulum membrane. Our recent work has shown that the spatial arrangement of RyR2s within clusters strongly influences the frequency of Ca2+ sparks. We showed that the probability of a Ca2+ spark occurring when a single RyR2 in the cluster opens spontaneously can be predicted from the precise spatial arrangements of the RyR2s. Thus, “function” follows from “structure.” This probability is related to the maximum eigenvalue (λ 1) of the adjacency matrix of the RyR2 cluster lattice. In this work, we develop a theoretical framework for understanding this relationship. We present a stochastic contact network model of the Ca2+ spark initiation process. We show that λ 1 determines a stability threshold for the formation of Ca2+ sparks in terms of the RyR2 gating transition rates. We recapitulate these results by applying the model to realistic RyR2 cluster structures informed by super-resolution stimulated emission depletion (STED) microscopy. Eigendecomposition of the linearized mean-field contact network model reveals functional subdomains within RyR2 clusters with distinct sensitivities to Ca2+. This work provides novel perspectives on the cardiac Ca2+ release process and a general method for inferring the functional properties of transmembrane receptor clusters from their structure. Many transmembrane receptors have been shown to aggregate into supramolecular clusters that enhance sensitivity to external stimuli in a variety of cell types. Advances in super-resolution microscopy have enabled researchers to study these structures with sufficient detail to distinguish the precise locations of individual receptors. In the heart, efforts have been successful in imaging calcium release channels, which are found in clusters of up to ∼ 100 in the sarcoplasmic reticulum membrane of cardiac myocytes. We showed in a recent study how the precise cluster structure affects the frequency of spontaneous release events known as calcium “sparks.” Here we have developed an analytical model of calcium spark initiation that clearly illustrates how the structure controls spark likelihood. We then applied this model to a collection of channel cluster structures obtained using super-resolution microscopy, revealing spatial gradients in the functional properties of individual channels. This work provides insight into the calcium release process in the heart and a framework for evaluating functional heterogeneity in populations of receptor clusters using structural information alone.