Department of Pharmacology, University of California Davis, Davis, CA.
Department of Pharmacology, University of California Davis, Davis, CA
J Am Heart Assoc. 2018 Jun 21;7(13):e008724. doi: 10.1161/JAHA.118.008724.
Ryanodine receptors (RyR) mediate sarcoplasmic reticulum calcium (Ca) release and influence myocyte Ca homeostasis and arrhythmias. In cardiac myocytes, RyRs are found in clusters of various sizes and shapes, and RyR cluster size may critically influence normal and arrhythmogenic Ca spark and wave formation. However, the actual RyR cluster sizes at specific Ca spark sites have never been measured in the physiological setting.
Here we measured RyR cluster size and Ca sparks simultaneously to assess how RyR cluster size influences Ca sparks and sarcoplasmic reticulum Ca leak. For small RyR cluster sizes (<50), Ca spark frequency is very low but then increases dramatically at larger cluster sizes. In contrast, Ca spark amplitude is nearly maximal even at relatively small RyR cluster size (≈10) and changes little at larger cluster size. These properties agreed with computational simulations of RyR gating within clusters.
Our study explains how this combination of properties may limit arrhythmogenic Ca sparks and wave propagation (at many junctions) while preserving the efficacy and spatial synchronization of Ca-induced Ca-release during normal excitation-contraction coupling. However, variations in RyR cluster size among individual junctions and RyR sensitivity could exacerbate heterogeneity of local sarcoplasmic reticulum Ca release and arrhythmogenesis under pathological conditions.
Ryanodine 受体 (RyR) 介导肌浆网钙 (Ca) 释放，并影响心肌细胞 Ca 稳态和心律失常。在心肌细胞中，RyR 存在于各种大小和形状的簇中，RyR 簇的大小可能会严重影响正常和致心律失常性 Ca 火花和波的形成。然而，在生理环境中，特定 Ca 火花位点的实际 RyR 簇大小从未被测量过。
在这里，我们同时测量 RyR 簇大小和 Ca 火花，以评估 RyR 簇大小如何影响 Ca 火花和肌浆网 Ca 泄漏。对于较小的 RyR 簇大小（<50），Ca 火花频率非常低，但在较大的簇大小下则会急剧增加。相比之下，即使在相对较小的 RyR 簇大小（≈10）时，Ca 火花幅度也几乎达到最大值，并且在较大的簇大小下变化很小。这些特性与 RyR 在簇内门控的计算模拟一致。
我们的研究解释了这种特性组合如何限制致心律失常性 Ca 火花和波的传播（在许多连接处），同时保持正常兴奋 - 收缩偶联期间 Ca 诱导的 Ca 释放的功效和空间同步性。然而，个体连接处 RyR 簇大小和 RyR 敏感性的变化可能会加剧病理条件下局部肌浆网 Ca 释放和心律失常的异质性。
