Department of Physiology and HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Department of Medicine and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
J Mol Cell Cardiol. 2023 Dec;185:38-49. doi: 10.1016/j.yjmcc.2023.10.012. Epub 2023 Oct 27.
The cardiac ryanodine receptor (RyR2) is an intracellular Ca release channel vital for the function of the heart. Physiologically, RyR2 is triggered to release Ca from the sarcoplasmic reticulum (SR) which enables cardiac contraction; however, spontaneous Ca leak from RyR2 has been implicated in the pathophysiology of heart failure (HF). RyR2 channels have been well documented to assemble into clusters within the SR membrane, with the organisation of RyR2 clusters recently gaining interest as a mechanism by which the occurrence of pathological Ca leak is regulated, including in HF. In this review, we explain the terminology relating to key nanoscale RyR2 clustering properties as both single clusters and functionally grouped Ca release units, with a focus on the advancements in super-resolution imaging approaches which have enabled the detailed study of cluster organisation. Further, we discuss proposed mechanisms for modulating RyR2 channel organisation and the debate regarding the potential impact of cluster organisation on Ca leak activity. Finally, recent experimental evidence investigating the nanoscale remodelling and functional alterations of RyR2 clusters in HF is discussed with consideration of the clinical implications.
心脏兰尼碱受体（RyR2）是一种细胞内钙离子释放通道，对心脏功能至关重要。在生理条件下，RyR2 被触发从肌浆网（SR）释放 Ca，从而使心脏收缩；然而，RyR2 的自发性 Ca 泄漏已被牵连到心力衰竭（HF）的病理生理学中。RyR2 通道已被充分记录为在 SR 膜内组装成簇，最近 RyR2 簇的组织作为调节病理性 Ca 泄漏发生的机制引起了人们的兴趣，包括在 HF 中。在这篇综述中，我们解释了与关键纳米级 RyR2 簇集特性相关的术语，包括单个簇和功能分组的 Ca 释放单元，重点介绍了超分辨率成像方法的进展，这些方法使对簇集组织的详细研究成为可能。此外，我们讨论了调节 RyR2 通道组织的拟议机制以及关于簇组织对 Ca 泄漏活性的潜在影响的争论。最后，讨论了 HF 中 RyR2 簇集的纳米级重塑和功能改变的最新实验证据，并考虑了其临床意义。
