Department of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Durham, NC 27710, USA.
Sci Signal. 2010 Jun 8;3(125):ra46. doi: 10.1126/scisignal.2000769.
beta-Arrestins, which were originally characterized as terminators of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) signaling, also act as important signal transducers. An emerging concept in GPCR signaling is beta-arrestin-biased agonism, in which specific ligand-activated GPCR conformational states selectively signal through beta-arrestins, rather than through G proteins. Here, we show that mechanical stretch induced beta-arrestin-biased signaling downstream of angiotensin II type I receptors (AT1Rs) in the absence of ligand or G protein activation. Mechanical stretch triggered an AT1R-mediated conformational change in beta-arrestin similar to that induced by a beta-arrestin-biased ligand to selectively stimulate receptor signaling in the absence of detectable G protein activation. Hearts from mice lacking beta-arrestin or AT1Rs failed to induce responses to mechanical stretch, as shown by blunted extracellular signal-regulated kinase and Akt activation, impaired transactivation of the epidermal growth factor receptor, and enhanced myocyte apoptosis. These data show that the heart responds to acute increases in mechanical stress by activating beta-arrestin-mediated cell survival signals.
β-arrestins 最初被描述为异三聚体鸟苷酸结合蛋白 (G 蛋白) - 偶联受体 (GPCR) 信号的终结者，也作为重要的信号转导器。GPCR 信号转导的一个新出现的概念是β-arrestin 偏向激动，其中特定的配体激活的 GPCR 构象状态通过β-arrestin 选择性地信号传递，而不是通过 G 蛋白。在这里，我们表明，在没有配体或 G 蛋白激活的情况下，机械拉伸诱导血管紧张素 II 型 1 型受体 (AT1R) 下游的β-arrestin 偏向信号转导。机械拉伸触发了与β-arrestin 偏向配体诱导的相似的 AT1R 介导的构象变化，以选择性地在没有可检测到的 G 蛋白激活的情况下刺激受体信号转导。缺乏β-arrestin 或 AT1R 的小鼠的心脏无法对机械拉伸做出反应，如细胞外信号调节激酶和 Akt 激活减弱、表皮生长因子受体的转激活受损以及心肌细胞凋亡增强所示。这些数据表明，心脏通过激活β-arrestin 介导的细胞存活信号来应对急性机械应激增加。
