Apelin-13 induces ERK1/2 but not p38 MAPK activation through coupling of the human apelin receptor to the Gi2 pathway
Apelin-13 induces ERK1/2 but not p38 MAPK activation through coupling of the human apelin receptor to the Gi2 pathway
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DOI：
10.1111/j.1745-7270.2008.00403.x
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发表时间：
2008-04-01
影响因子：
3.7
通讯作者：
Song, Wengang
中科院分区：
文献类型：
--
作者：
Bai, Bo;Tang, Jiyou;Song, Wengang
爱帕琳通过爱帕琳受体（apelin receptor，APJ）与G蛋白的偶联，向丝裂原活化蛋白激酶（mitogen-activated protein kinases，MAPKs）家族如细胞外调节激酶1/2（extracellular-regulated kinases 1/2，ERK 1/2）和p38 MAPK发出信号，介导重要的病理生理反应。虽然已经报道了爱帕琳肽片段通过G（i）-蛋白诱导ERK 1/2活化，但APJ活化这些MAPK的细胞内途径仅被部分理解。在这里，使用稳定转染的人胚肾293（HEK 293）细胞过表达人APJ（HEK 293-apelinR），我们发现apelin-13信号转导通过APJ激活导致ERK 1/2和p38 MAPK通路。在HEK 293-apelinR细胞中发现，爱帕琳-13在5 min时启动ERK 1/2激活，在15 min时出现激活峰值，并在60 min内恢复到基础水平。ERK 1/2的激活似乎具有剂量依赖性，在10 nM爱帕琳-13时观察到显著激活，在100 nM时观察到最大激活。然而，在用爱帕琳-13处理的HEK 293-爱帕琳R细胞中未检测到磷酸化p38 MAPK。我们还表明，爱帕琳-13诱导的ERK 1/2激活需要与百日咳毒素敏感的G蛋白偶联，并且显性负性G（i2）的过表达完全抑制爱帕琳-13诱导的ERK 1/2激活。此外，用爱帕琳-13处理导致毛喉素刺激的cAMP产生的浓度依赖性减少。因此表明爱帕琳-13激活ERK 1/2而不是p38 MAPK，其涉及APJ与G（i2）级联的偶联。总之，ERK 1/2而不是p38 MAPK通路通过人APJ与G（i2）-蛋白的偶联被爱帕琳-13激活，这有助于细胞应答。
Apelin signaling to the family of mitogen-activated protein kinases (MAPKs), such as extracellular-regulated kinases 1/2 (ERK1/2) and p38 MAPK, through the coupling of apelin receptor (APJ) to G-protein, mediates important pathophysiological responses. Although apelin fragments have been reported to induce ERK1/2 activation through G(i)-protein, the intracellular pathways by which APJ activates these MAPKs are only partially understood. Here, using stably transfected human embryonic kidney 293 (HEK293) cells overexpressing human APJ (HEK293-apelinR), we showed that apelin-13 signaling leads to ERK1/2 and p38 MAPK pathways through APJ activation. It was found in HEK293-apelinR cells that ERK1/2 activation was initiated by apelin-13 at 5 min, with the peak of activation occurring at 15 min, and a return to the basal level within 60 min. The activation of ERK1/2 appeared to be dose-dependent with a significant activation being observed at 10 nM apelin-13 and maximal activation at 100 nM. However, phosphorylated-p38 MAPK was not detected in HEK293-apelinR cells treated with apelin-13. We also shown that the apelin-13-induced ERK1/2 activation requires a coupling with pertussis toxin-sensitive G-protein, and that overexpression of dominant-negative G(i2) completely inhibits the apelin-13-induced ERK1/2 activation. In addition, treatment with apelin-13 resulted in a concentration-dependent reduction of forskolin-stimulated cAMP production. It is therefore suggested that apelin-13 activates ERK1/2 but not p38 MAPK, which involves the coupling of APJ to the G(i2) cascade. In conclusion, the ERK1/2, but not p38 MAPK pathway is activated by apelin-13 through coupling of human APJ to G(i2)-protein, which contributes to cellular responses.