Lang Di, Glukhov Alexey V
Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States.
Front Physiol. 2018 Nov 27;9:1686. doi: 10.3389/fphys.2018.01686. eCollection 2018.
Spontaneous beating of the sinoatrial node (SAN), the primary pacemaker of the heart, is initiated, sustained, and regulated by a complex system that integrates ion channels and transporters on the cell membrane surface (often referred to as "membrane clock") with subcellular calcium handling machinery (by parity of reasoning referred to as an intracellular "Ca clock"). Stable, rhythmic beating of the SAN is ensured by a rigorous synchronization between these two clocks highlighted in the coupled-clock system concept of SAN timekeeping. The emerging results demonstrate that such synchronization of the complex pacemaking machinery at the cellular level depends on tightly regulated spatiotemporal signals which are restricted to precise sub-cellular microdomains and associated with discrete clusters of different ion channels, transporters, and regulatory receptors. It has recently become evident that within the microdomains, various proteins form an interacting network and work together as a part of a macromolecular signaling complex. These protein-protein interactions are tightly controlled and regulated by a variety of neurohormonal signaling pathways and the diversity of cellular responses achieved with a limited pool of second messengers is made possible through the organization of essential signal components in particular microdomains. In this review, we highlight the emerging understanding of the functionality of distinct subcellular microdomains in SAN myocytes and their functional role in the accumulation and neurohormonal regulation of proteins involved in cardiac pacemaking. We also demonstrate how changes in scaffolding proteins may lead to microdomain-targeted remodeling and regulation of pacemaker proteins contributing to SAN dysfunction.
心脏的主要起搏点——窦房结（SAN）的自发搏动，是由一个复杂的系统启动、维持和调节的，该系统将细胞膜表面的离子通道和转运体（通常称为“膜时钟”）与亚细胞钙处理机制（同理称为细胞内“钙时钟”）整合在一起。窦房结稳定、有节律的搏动是由这两个时钟之间严格的同步来确保的，这在窦房结计时的耦合时钟系统概念中得到了强调。新出现的结果表明，这种复杂的起搏机制在细胞水平上的同步依赖于严格调控的时空信号，这些信号局限于精确的亚细胞微区，并与不同离子通道、转运体和调节受体的离散簇相关联。最近已经很明显，在这些微区内，各种蛋白质形成一个相互作用的网络，并作为大分子信号复合物的一部分协同工作。这些蛋白质-蛋白质相互作用受到多种神经激素信号通路的严格控制和调节，通过在特定微区组织基本信号成分，利用有限的第二信使池实现细胞反应的多样性成为可能。在这篇综述中，我们重点介绍了对窦房结心肌细胞中不同亚细胞微区功能的新认识，以及它们在心脏起搏相关蛋白质的积累和神经激素调节中的功能作用。我们还展示了支架蛋白的变化如何导致针对微区的重塑和对起搏蛋白的调节，从而导致窦房结功能障碍。
