Compartmentalized β1-Adrenergic Signaling Synchronizes Excitation-contraction Coupling Without Modulating Individual Ca2+ Sparks in Healthy and Hypertrophied Cardiomyocytes.
Compartmentalized β1-Adrenergic Signaling Synchronizes Excitation-contraction Coupling Without Modulating Individual Ca2+ Sparks in Healthy and Hypertrophied Cardiomyocytes.
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DOI：
10.1093/cvr/cvaa013
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发表时间：
2020-02
影响因子：
10.8
通讯作者：
Hua-Qian Yang;Peng Zhou;Li-Peng Wang;Yan-Ting Zhao;Yu-Jie Ren;Yun-Bo Guo;Ming Xu;Shi-Qiang Wang
中科院分区：
文献类型：
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作者：
Hua-Qian Yang;Peng Zhou;Li-Peng Wang;Yan-Ting Zhao;Yu-Jie Ren;Yun-Bo Guo;Ming Xu;Shi-Qiang Wang
AIMS β-肾上腺素能受体 (βAR) 在调节心脏兴奋-收缩 (E-C) 耦合中发挥着关键作用。 β1AR 的整体信号传导上调通过肌膜 L 型 Ca2+ 通道 (LCC) 的 Ca2+ 流入以及通过兰尼碱受体 (RyRs) 从肌浆网 (SR) 释放 Ca2+。然而，我们最近发现 β2AR 刺激会导致“越位区室化”，将 β1AR 信号限制在肌膜下纳米结构域中，而不会到达 SR 蛋白。在本研究中，我们旨在研究分隔的 β1AR 信号传导是否以及如何调节心脏 E-C 耦合的新问题。方法和结果 通过结合共聚焦 Ca2+ 成像和膜片钳技术，我们研究了区室化 βAR 信号传导对细胞和分子水平 E-C 耦合的影响。我们发现，与 β1AR 的全局信号传导相反，β2 和 β1AR 的同时激活既不调节 Ca2+ 火花的幅度和时空特性，也不调节 RyR 对 LCC Ca2+ 火花的响应动力学。然而，通过上调 LCC 电流，分隔的 β1AR 信号同步 RyR Ca2+ 释放并增加 E-C 耦合的功能储备（稳定裕度）。在激发持续时间较短或 RyR 响应性较低的情况下，通过增加 Ca2+ 触发强度，区室化 βAR 信号传导有助于稳定 E-C 耦合的性能并增强衰竭心脏细胞中的 Ca2+ 瞬态振幅。结论 鉴于与压力相关的儿茶酚胺水平可以诱导区室化 βAR 信号传导，我们的结果揭示了一种重要但未被重视的心脏调节机制，该机制可自动适应不同的压力条件。
AIMS β-Adrenergic receptors (βARs) play pivotal roles in regulating cardiac excitation-contraction (E-C) coupling. Global signaling of β1ARs upregulates both the influx of Ca2+ through sarcolemmal L-type Ca2+ channels (LCCs) and the release of Ca2+ from the sarcoplasmic reticulum (SR) through the ryanodine receptors (RyRs). However, we recently found that β2AR stimulation meditates "offside compartmentalization", confining β1AR signaling into subsarcolemmal nanodomains without reaching SR proteins. In the present study, we aim to investigate the new question whether and how compartmentalized β1AR signaling regulates cardiac E-C coupling. METHODS AND RESULTS By combining confocal Ca2+ imaging and patch clamp techniques, we investigated the effects of compartmentalized βAR signaling on E-C coupling at both cellular and molecular levels. We found that simultaneous activation of β2 and β1ARs, in contrast to global signaling of β1ARs, modulated neither the amplitude and spatiotemporal properties of Ca2+ sparks nor the kinetics of the RyR response to LCC Ca2+ sparklets. Nevertheless, by upregulating LCC current, compartmentalized β1AR signaling synchronized RyR Ca2+ release and increased the functional reserve (stability margin) of E-C coupling. In circumstances of briefer excitation durations or lower RyR responsivity, compartmentalized βAR signaling, by increasing the intensity of Ca2+ triggers, helped stabilize the performance of E-C coupling and enhanced the Ca2+ transient amplitude in failing heart cells. CONCLUSION Given that compartmentalized βAR signaling can be induced by stress-associated levels of catecholamines, our results revealed an important, yet unappreciated, heart regulation mechanism that is autoadaptive to varied stress conditions.