Probing spatiotemporal PKA activity at the ryanodine receptor and SERCA2a nanodomains in cardomyocytes.
Probing spatiotemporal PKA activity at the ryanodine receptor and SERCA2a nanodomains in cardomyocytes.
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DOI：
10.1186/s12964-022-00947-8
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发表时间：
2022-09-14
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亚细胞蛋白激酶A（PKA）活性的时空调节，精确的底物磷酸化是细胞对激素刺激的反应所必需的。Ryanodine receptor 2（RyR 2）和（sarco）endoplasmic reticulum calcium ATPase 2a（SERCA 2a）是肌浆网膜β肾上腺素受体（βAR）信号传导的两个关键靶点，用于心脏兴奋和收缩偶联。而β2AR信号传导受限于这些纳米结构域。磷酸二酯酶4（PDE 4）和PDE 3控制基线PKA活性并阻止β2AR信号传导到达RyR 2和SERCA 2a纳米结构域。此外，阻断抑制性G蛋白允许β2AR信号传导至RyR 2而不是SERCA 2a纳米结构域。这项研究为抑制性G蛋白和PDE在控制心肌细胞中RyR 2和SERCA 2a纳米结构域的肾上腺素能亚型信号传导中的不同作用提供了证据。视频摘要在线版本包含补充材料，可在10. 1186/s12964-022-00947-8。设计基于FRET的生物传感器以监测肌细胞中RyR 2纳米结构域处的PKA动力学。β 1 AR的刺激促进RyR 2和SERCA 2a纳米结构域处的PKA活性，而β 2 AR的刺激不促进PKA活性。在线版本包含补充材料，可通过10.1186/s12964-022-00947-8获取。
Spatiotemporal regulation of subcellular protein kinase A (PKA) activity for precise substrate phosphorylation is essential for cellular responses to hormonal stimulation. Ryanodine receptor 2 (RyR2) and (sarco)endoplasmic reticulum calcium ATPase 2a (SERCA2a) represent two critical targets of β adrenoceptor (βAR) signaling on the sarcoplasmic reticulum membrane for cardiac excitation and contraction coupling. Using novel biosensors, we show that cardiac β1AR signals to both RyR2 and SERCA2a nanodomains in cardiomyocytes from mice, rats, and rabbits, whereas the β2AR signaling is restricted from these nanodomains. Phosphodiesterase 4 (PDE4) and PDE3 control the baseline PKA activity and prevent β2AR signaling from reaching the RyR2 and SERCA2a nanodomains. Moreover, blocking inhibitory G protein allows β2AR signaling to the RyR2 but not the SERCA2a nanodomains. This study provides evidence for the differential roles of inhibitory G protein and PDEs in controlling the adrenergic subtype signaling at the RyR2 and SERCA2a nanodomains in cardiomyocytes. Video abstract The online version contains supplementary material available at 10.1186/s12964-022-00947-8. Design a FRET-based biosensor to monitor PKA dynamics at the RyR2 nanodomains in myocytes Stimulation of β1AR promotes PKA activity at both RyR2 and SERCA2a nanodomains whereas stimulation of β2AR does not Inhibition of PDE3 and PDE4 enhances PKA activity at the baseline and after β2AR stimulation Inhibition of Gi selectively permits β2AR signaling to the RyR2 nanodomains but not SERCA2a nanodomains. The online version contains supplementary material available at 10.1186/s12964-022-00947-8.
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