CP-25 inhibits the hyperactivation of rheumatic synoviocytes by suppressing the switch in G(αs)-G(αi) coupling to the β(2)-adrenergic receptor.
CP-25 inhibits the hyperactivation of rheumatic synoviocytes by suppressing the switch in G(αs)-G(αi) coupling to the β(2)-adrenergic receptor.
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DOI：
10.1186/s12964-023-01358-z
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发表时间：
2023-11-30
影响因子：
8.4
通讯作者：
Wang, Qingtong
中科院分区：
文献类型：
--
作者：
Ge, Mingli;Wu, Li;He, Feng;Tai, Yu;Fang, Ruhong;Han, Dafei;Guo, Paipai;Liu, Hao;Hu, Yong;Xu, Shenglin;Wei, Wei;Wang, Qingtong
关键词：
β2肾上腺素能受体（β2 adrenergic receptor，β 2 AR）通过Gαs偶联增加细胞内环磷酸腺苷（cyclic 3 '，5'-adenosine monophosphate，cAMP）浓度，发挥抗增殖作用，但有趣的是，β 2 AR拮抗剂能有效抑制成纤维细胞样滑膜细胞（fibroblast like synoviocytes，FLS）增殖，从而改善实验性RA，表明β 2 AR信号通路在RA FLS中通过未知机制受损。炎症关节中局部肾上腺素（Epi）水平远高于正常关节，高水平的Epi或异丙肾上腺素（ISO）刺激直接促进FLS增殖和迁移，这是由于β 2 AR信号转导和cAMP产生受损所致。应用受体内化抑制剂、Gαs和Gαi的小干扰RNA（siRNA）、荧光共振能量转移和免疫共沉淀技术，观察到炎症性FLS和慢性ISO刺激FLS中Gαs-Gαi偶联β 2 AR的开关。这种Gαi偶联是由G蛋白偶联受体激酶2（GRK 2）启动的，而不是由β-arrestin 2或蛋白激酶A介导的β2AR磷酸化启动的。用新型GRK 2抑制剂芍药苷-6 ′-O-苯磺酸酯（CP-25）或公认的GRK 2抑制剂帕罗西汀抑制GRK 2活性，可有效逆转炎症过程中Gαs-Gαi偶联至β 2 AR的转换，并恢复ISO刺激的FLS细胞内cAMP水平。正如预期的那样，CP-25显著抑制胶原诱导的关节炎（CIA）模型（CIA FLS）和ISO刺激的正常FLS的增生，并最终改善大鼠的CIA。总之，我们的研究结果揭示了CIA FLS中β2AR信号的病理变化，确定了潜在的机制，并确定了GRK 2抑制剂CP-25治疗CIA的药理学靶点。视频摘要在线版本包含补充材料，可通过10. 1186/s12964-023-01358-z获取。
In essence, the β2 adrenergic receptor (β2AR) plays an antiproliferative role by increasing the intracellular cyclic 3’,5’-adenosine monophosphate (cAMP) concentration through Gαs coupling, but interestingly, β2AR antagonists are able to effectively inhibit fibroblast-like synoviocytes (FLSs) proliferation, thus ameliorating experimental RA, indicating that the β2AR signalling pathway is impaired in RA FLSs via unknown mechanisms. The local epinephrine (Epi) level was found to be much higher in inflammatory joints than in normal joints, and high-level stimulation with Epi or isoproterenol (ISO) directly promoted FLSs proliferation and migration due to impaired β2AR signalling and cAMP production. By applying inhibitor of receptor internalization, and small interfering RNA (siRNA) of Gαs and Gαi, and by using fluorescence resonance energy transfer and coimmunoprecipitation assays, a switch in Gαs-Gαi coupling to β2AR was observed in inflammatory FLSs as well as in FLSs with chronic ISO stimulation. This Gαi coupling was then revealed to be initiated by G protein coupled receptor kinase 2 (GRK2) but not β-arrestin2 or protein kinase A-mediated phosphorylation of β2AR. Inhibiting the activity of GRK2 with the novel GRK2 inhibitor paeoniflorin-6′-O-benzene sulfonate (CP-25), a derivative of paeoniflorin, or the accepted GRK2 inhibitor paroxetine effectively reversed the switch in Gαs-Gαi coupling to β2AR during inflammation and restored the intracellular cAMP level in ISO-stimulated FLSs. As expected, CP-25 significantly inhibited the hyperplasia of FLSs in a collagen-induced arthritis (CIA) model (CIA FLSs) and normal FLSs stimulated with ISO and finally ameliorated CIA in rats. Together, our findings revealed the pathological changes in β2AR signalling in CIA FLSs, determined the underlying mechanisms and identified the pharmacological target of the GRK2 inhibitor CP-25 in treating CIA. Video Abstract The online version contains supplementary material available at 10.1186/s12964-023-01358-z.
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