Go/Gi coupled G-protein receptor mediated transactivation is critical in the activation of receptor tyrosine kinases (RTK). Here we show that mu opioid receptor (MOR) transactivates Flk1 and platelet-derived growth factor-beta (PDGF-beta) receptors and its agonist morphine stimulates pro-angiogenic and survival-promoting signaling in mouse retinal endothelial cells (mREC). Morphine stimulates mREC proliferation in a dose dependent fashion and promotes survival to the same extent as vascular endothelial growth factor164 (VEGF164). Morphine stimulates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt phosphorylation in a time dependent manner like VEGF in mREC. Moreover, analogous to VEGF, morphine stimulates oncogenic signal transducer and activator of transcription 3 (STAT3) signaling. Morphine as well as VEGF-induced phospho-STAT3 and phospho-Flk1 immunoprecipitated with MOR-associated proteins. In addition morphine also stimulated MOR associated PDGF-beta receptor phosphorylation. Consistent with the relationship between VEGF and MOR we found that VEGF upregulates MOR protein and RNA expression in mREC. These data suggest that MOR associates and transactivates RTKs for Flk1 and PDGF-beta, which may have a compounding effect on angiogenic signaling in endothelium. Therefore, G-Protein coupled receptors including MOR provide novel targets to develop anti-angiogenic agents.

译文

Go/Gi偶联的g蛋白受体介导的反式激活在受体酪氨酸激酶 (RTK) 的激活中至关重要。在这里,我们显示mu阿片受体 (MOR) 反式激活Flk1和血小板衍生的生长因子-β (pdgf-β) 受体及其激动剂吗啡刺激小鼠视网膜内皮细胞 (mREC) 中的促血管生成和促进存活的信号。吗啡以剂量依赖性方式刺激mREC增殖,并以与血管内皮生长因子164 (VEGF164) 相同的程度促进存活。吗啡以时间依赖性方式刺激丝裂原激活的蛋白激酶/细胞外信号调节激酶 (MAPK/ERK) 和Akt磷酸化,如mREC中的VEGF。此外,与VEGF类似,吗啡刺激致癌信号转导和转录激活因子3 (STAT3) 信号传导。吗啡以及VEGF诱导的phospho-STAT3和phospho-Flk1用MOR相关蛋白免疫沉淀。此外,吗啡还刺激MOR相关的PDGF-β 受体磷酸化。与VEGF和MOR之间的关系一致,我们发现VEGF上调了MOR蛋白和RNA在mREC中的表达。这些数据表明,MOR关联并反式激活了Flk1和PDGF-β 的RTKs,这可能对内皮中的血管生成信号传导具有复合作用。因此,包括MOR在内的g蛋白偶联受体为开发抗血管生成剂提供了新的靶标。

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