β-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling
β-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling
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DOI：
10.1038/emboj.2009.215
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发表时间：
2009-09-16
期刊：
影响因子：
11.4
通讯作者：
Dumuis, Aline
中科院分区：
文献类型：
--
作者：
Barthet, Gael;Carrat, Gaelle;Dumuis, Aline
已发现G蛋白偶联受体（gpcr）可触发G蛋白非依赖性信号传导。然而，对G蛋白非依赖性通路的调控，特别是其脱敏作用的描述很少。在这里，我们发现G蛋白独立的5- ht4受体（5- ht4r）操作的Src/ERK（细胞外信号调节激酶）途径，而不是G(s)途径，被GPCR激酶5 （GRK5）抑制，在人胚胎肾(HEK)-293细胞和丘丘神经元中，GRK5与受体c端近端区域物理相关。这种抑制需要两个事件序列：β -arrestin1与受体C-t结构域中磷酸化的丝氨酸/苏氨酸簇相关联，以及GRK5磷酸化β -arrestin1（在Ser（412）处）与受体结合。磷酸化的β -arrestin1反过来阻止了Src与5-HT(4)Rs组成结合的激活，这是受体刺激的ERK信号传导的必要步骤。这是GRK5对β -arrestin1磷酸化调控G蛋白非依赖性信号传导的首次证明。EMBO学报，2009,28,2706-2718。doi: 10.1038 / emboj.2009.215;2009年8月6日在线发布
G protein-coupled receptors (GPCRs) have been found to trigger G protein-independent signalling. However, the regulation of G protein-independent pathways, especially their desensitization, is poorly characterized. Here, we show that the G protein-independent 5-HT4 receptor (5-HT4R)-operated Src/ERK (extracellular signal-regulated kinase) pathway, but not the G(s) pathway, is inhibited by GPCR kinase 5 (GRK5), physically associated with the proximal region of receptor' C-terminus in both human embryonic kidney (HEK)-293 cells and colliculi neurons. This inhibition required two sequences of events: the association of beta-arrestin1 to a phosphorylated serine/threonine cluster located within the receptor C-t domain and the phosphorylation, by GRK5, of beta-arrestin1 (at Ser(412)) bound to the receptor. Phosphorylated beta-arrestin1 in turn prevented activation of Src constitutively bound to 5-HT(4)Rs, a necessary step in receptor-stimulated ERK signalling. This is the first demonstration that beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent signalling. The EMBO Journal (2009) 28, 2706-2718. doi: 10.1038/emboj.2009.215; Published online 6 August 2009