beta2-Adrenergic Stimulation Compartmentalizes beta1 Signaling Into Nanoscale Local Domains by Targeting the C-Terminus of beta1-Adrenoceptors.
beta2-Adrenergic Stimulation Compartmentalizes beta1 Signaling Into Nanoscale Local Domains by Targeting the C-Terminus of beta1-Adrenoceptors.
复制标题
beta(2)-肾上腺素刺激通过靶向 beta(1)-肾上腺素受体的 C 末端将 beta(1) 信号传导划分为纳米级局部域
DOI：
10.1161/circresaha.118.314322
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发表时间：
2019
影响因子：
20.1
通讯作者：
Wang Shi-Qiang
中科院分区：
文献类型：
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作者：
Yang Hua-Qian;Wang Li-Peng;Gong Yun-Yun;Fan Xue-Xin;Zhu Si-Yu;Wang Xiao-Ting;Wang Yu-Pu;Li Lin-Lin;Xing Xin;Liu Xiao-Xiao;Ji Guang-Shen;Hou TingTing;Zhang Yan;Xiao Rui-Ping;Wang Shi-Qiang
原理：β AR（β-肾上腺素能受体）是原型GPCR（G蛋白偶联受体），在交感神经调节中发挥关键作用。在心脏细胞中，β 1 AR信号介导了一个整体反应，包括肌膜/T小管中的I型Ca 2+通道和SR（肌浆网）中的RyR（ryanodine受体）。目的：探讨β1ARs和β 2ARs之间的信号转导关系。方法：采用全细胞膜片钳技术结合共聚焦钙离子成像技术，研究β2AR信号转导通路的激活，发现β2AR信号转导通路的激活可以将β1AR信号转导通路从整体模式转变为局部模式，阻止β1ARs磷酸化距离肌膜/T小管仅几纳米的RyR。通过选择性抑制β2AR、GRK 2（GPCR激酶-2）、β arr 1（β-arrestin-1）和磷酸二酯酶-4消除这种越位区室化。结论：β 2 AR刺激通过磷酸二酯酶-4依赖性靶向β 1ARs的C端，将β 1ARs信号区隔成纳米级的局部区域，β 1ARs C端的最后3个丝氨酸残基（β arr 1结合位点和GRK 2磷酸化位点的一个组成部分）突变的敲入大鼠模型消除了β 2 AR激活所引起的越位区隔。这一发现揭示了一种基本的负前馈机制，该机制用于避免循环儿茶酚胺的细胞毒性，并使交感兴奋的瞬时β 1 AR反应变得尖锐。
Rationale:βARs (β-adrenergic receptors) are prototypical GPCRs (G protein–coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, β1AR signaling mediates a global response, including bothl-type Ca2+channels in the sarcolemma/T tubules and RyRs (ryanodine receptors) in the SR (sarcoplasmic reticulum). In contrast, β2AR mediates local signaling with little effect on the function of SR proteins.Objective:To investigate the signaling relationship between β1ARs and β2ARs.Method and Results:Using whole-cell patch-clamp analyses combined with confocal Ca2+imaging, we found that the activation of compartmentalized β2AR signaling was able to convert the β1AR signaling from global to local mode, preventing β1ARs from phosphorylating RyRs that were only nanometers away from sarcolemma/T tubules. This offside compartmentalization was eliminated by selective inhibition of β2AR, GRK2 (GPCR kinase-2), βarr1 (β-arrestin-1), and phosphodiesterase-4. A knockin rat model harboring mutations of the last 3 serine residues of the β1AR C terminus, a component of the putative βarr1 binding site and GRK2 phosphorylation site, eliminated the offside compartmentalization conferred by β2AR activation.Conclusions:β2AR stimulation compartmentalizes β1AR signaling into nanoscale local domains in a phosphodiesterase-4–dependent manner by targeting the C terminus of β1ARs. This finding reveals a fundamental negative feed-forward mechanism that serves to avoid the cytotoxicity of circulating catecholamine and to sharpen the transient β1AR response of sympathetic excitation.