Junctophilin-2 in the nanoscale organisation and functional signalling of ryanodine receptor clusters in cardiomyocytes
Junctophilin-2 in the nanoscale organisation and functional signalling of ryanodine receptor clusters in cardiomyocytes
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Junctophilin-2 在心肌细胞中兰尼碱受体簇的纳米级组织和功能信号传导中的作用。
DOI：
10.1242/jcs.196873
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发表时间：
2016-12-01
影响因子：
4
通讯作者：
Soeller, Christian
中科院分区：
文献类型：
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作者：
Munro, Michelle L.;Jayasinghe, Isuru D.;Soeller, Christian
需要质膜和内部隔室之间的紧密接触的信号传导纳米结构域（称为“接头”）是可兴奋细胞（如神经元和肌肉）内的快速通信枢纽。在这里，我们已经研究了两个转基因小鼠模型探测junctophilin-2的作用，膜拴系蛋白的形成和心脏的心室肌细胞的亚显微连接的分子组织至关重要。定量单分子定位显微镜显示，在动物生产高于正常水平的junctophilin-2的路口扩大，允许重组的主要功能蛋白质内，Ryanodine受体（RyR;在本文中，我们使用RyR指的是心肌亚型RyR 2）。虽然这种变化与放大的RyR簇有关，由于它们的大小，应该更兴奋，但在功能上，它引起了连接处的Ca 2+信号输出（Ca 2+火花）的轻度抑制。RyR和junctophilin-2的单分子密度的分析揭示了类似的3倍增加的junctophilin-2的RyR比率。这种分子重排与亲连接蛋白-2直接抑制RyR开放相容，从而内在地稳定连接的Ca 2+信号传导特性，从而稳定细胞的收缩功能。
Signalling nanodomains requiring close contact between the plasma membrane and internal compartments, known as 'junctions', are fast communication hubs within excitable cells such as neurones and muscle. Here, we have examined two transgenic murine models probing the role of junctophilin-2, a membrane-tethering protein crucial for the formation and molecular organisation of submicroscopic junctions in ventricular muscle cells of the heart. Quantitative single-molecule localisation microscopy showed that junctions in animals producing above-normal levels of junctophilin-2 were enlarged, allowing the re-organisation of the primary functional protein within it, the ryanodine receptor (RyR; in this paper, we use RyR to refer to the myocardial isoform RyR2). Although this change was associated with much enlarged RyR clusters that, due to their size, should be more excitable, functionally it caused a mild inhibition in the Ca2+ signalling output of the junctions (Ca2+ sparks). Analysis of the single-molecule densities of both RyR and junctophilin-2 revealed an similar to 3-fold increase in the junctophilin-2 to RyR ratio. This molecular rearrangement is compatible with direct inhibition of RyR opening by junctophilin-2 to intrinsically stabilise the Ca2+ signalling properties of the junction and thus the contractile function of the cell.