5-HT1A receptor-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) is modulated by regulator of G protein signaling protein 19.
5-HT1A receptor-mediated phosphorylation of extracellular signal-regulated kinases (ERK1/2) is modulated by regulator of G protein signaling protein 19.
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DOI：
10.1016/j.cellsig.2014.04.017
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发表时间：
2014-09
影响因子：
4.8
通讯作者：
Traynor JR
中科院分区：
文献类型：
--
作者：
Wang Q;Terauchi A;Yee CH;Umemori H;Traynor JR
5-HT 1A受体是一种G蛋白偶联受体（GPCR），可激活Gαi/o家族的G蛋白。中缝、海马和前额皮质中表达的5-HT 1A受体与情绪控制有关，并且是抗抑郁药物的靶点。G蛋白信号调节蛋白（Regulators of G protein signaling，RGS）是G蛋白偶联受体（G protein coupled receptor，GPCRs）下游信号转导的重要蛋白家族。RGS蛋白的主要作用是作为GT3加速蛋白（GAP）来抑制或负调节GPCR介导的信号传导。我们已经表明，表达Gαi2的小鼠对所有RGS蛋白GAP活性不敏感，由于突触后5-HT 1A受体的信号传导增加，具有抗β-样表型，因此暗示5-HT 1A受体-G αi2复合物是重要的靶点。在这里，我们证实，RGS蛋白作为GAP调节信号转导腺苷酸环化酶和丝裂原活化蛋白激酶（MAPK）途径下游的5-HT 1A受体，使用RGS不敏感的Gαi2蛋白在C6细胞中表达。我们继续使用短发夹RNA（shRNA）来显示RGS 19负责C6细胞中差距活性，并且RGS 19在人神经母细胞瘤SH-SY 5 Y细胞和原代海马神经元中充当5-HT 1A受体信号传导的GAP。此外，在这两种细胞类型中，5-HT 1A受体和成纤维细胞生长因子受体1在刺激MAPK途径中的协同作用在RGS 19表达的shRNA减少后增强。因此，RGS 19可能是一个可行的新靶点抗肿瘤药物。
The 5-HT1A receptor is a G protein coupled receptor (GPCR) that activates G proteins of the Gαi/o family. 5-HT1A receptors expressed in the raphe, hippocampus and prefrontal cortex are implicated in the control of mood and are targets for anti-depressant drugs. Regulators of G protein signaling (RGS) proteins are members of a large family that play important roles in signal transduction downstream of G protein coupled receptors (GPCRs). The main role of RGS proteins is to act as GTPase accelerating proteins (GAPs) to dampen or negatively regulate GPCR-mediated signaling. We have shown that a mouse expressing Gαi2 that is insensitive to all RGS protein GAP activity has an anti-depressant-like phenotype due to increased signaling of postsynaptic 5-HT1A receptors, thus implicating the 5-HT1A receptor–Gαi2 complex as an important target. Here we confirm that RGS proteins act as GAPs to regulate signaling to adenylate cyclase and the mitogen-activated protein kinase (MAPK) pathway downstream of the 5-HT1A receptor, using RGS-insensitive Gαi2 protein expressed in C6 cells. We go on to use short hairpin RNA (shRNA) to show that RGS19 is responsible for the GAP activity in C6 cells and also that RGS19 acts as a GAP for 5-HT1A receptor signaling in human neuroblastoma SH-SY5Y cells and primary hippocampal neurons. In addition, in both cell types the synergy between 5-HT1A receptor and the fibroblast growth factor receptor 1 in stimulating the MAPK pathway is enhanced following shRNA reduction of RGS19 expression. Thus RGS19 may be a viable new target for anti-depressant medications.
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