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Angiotensin (1–7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor
Cellular Signalling ( IF 4.4 ) Pub Date : 2018-06-19 , DOI: 10.1016/j.cellsig.2018.06.007
Ibragim Gaidarov , John Adams , John Frazer , Todd Anthony , Xiaohua Chen , Joel Gatlin , Graeme Semple , David J. Unett

Angiotensin (1–7) has been reported to be a ligand for the GPCR MAS1. Small molecule MAS1 modulators have also been recently characterized. Aside from convincing evidence for MAS1 activation of Gq signaling, little is known about MAS1 mediated signaling pathways initiated by these ligands, especially Ang (1–7). We performed a comprehensive characterization of recombinant MAS1 signaling induced by Ang (1–7) and small molecule ligands through numerous G protein-dependent and independent pathways, and in a signaling pathway agnostic approach. We find that small molecule ligands modulate numerous G protein-dependent and independent pathways through MAS1, including Gq and Gi pathways, GTPγS binding, β-arrestin recruitment, Erk1/2 and Akt phosphorylation, arachidonic acid release, and receptor internalization. Moreover, in dynamic mass redistribution (DMR) assays that provide a pathway-agnostic readout of cellular responses, small molecule agonists produced robust responses. In contrast, Ang (1–7) failed to induce or block signaling in any of these assay platforms. We detected specific binding of radiolabeled Ang (1–7) to rat aortic endothelial cell (RAEC) membranes, but not to recombinant MAS1. Biphasic, concentration-dependent biased signaling responses to Ang II were detected in RAEC. These phases were associated with vastly different DMR characteristics and this likely provides a molecular basis for previously observed concentration-dependent divergent physiological actions of Ang II. Both phases of Ang II signaling in RAECs were potently inhibited by Ang (1–7), providing a plausible molecular mechanism for Ang (1–7) as counter regulator of the Ang II- AT1 axis, responsible at least in part for Ang (1–7) physiological activities.



中文翻译:

血管紧张素(1–7)不与MAS1直接相互作用,但可以有效拮抗AT1受体的信号传导

据报道,血管紧张素(1–7)是GPCR MAS1的配体。小分子MAS1调节剂最近也已被表征。除了令人信服的有关MAS1激活Gq信号的证据外,关于由这些配体特别是Ang(1–7)引发的MAS1介导的信号传导途径知之甚少。我们对Ang(1–7)和小分子配体通过许多G蛋白依赖性和独立途径诱导的重组MAS1信号传导进行了全面表征,并采用了与信号传导途径无关的方法。我们发现小分子配体通过MAS1调节许多G蛋白依赖性和独立途径,包括Gq和Gi途径,GTPγS结合,β-arrestin募集,Erk1 / 2和Akt磷酸化,花生四烯酸释放和受体内化。而且,在动态质量重新分配(DMR)分析中,该方法提供了与细胞反应无关的途径读数,小分子激动剂产生了稳定的反应。相反,Ang(1–7)在任何这些测定平台中均无法诱导或阻断信号传导。我们检测到放射性标记的Ang(1–7)与大鼠主动脉内皮细胞(RAEC)膜的特异性结合,但未与重组MAS1结合。在RAEC中检测到对Ang II的双相,浓度依赖性的偏向信号传导反应。这些阶段与完全不同的DMR特征相关,这可能为先前观察到的Ang II浓度依赖性发散的生理作用提供了分子基础。RAEC中的Ang II信号的两个阶段均被Ang(1–7)抑制,

更新日期:2018-06-19
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