期刊
EMBO JOURNAL
卷 28, 期 18, 页码 2706-2718出版社
WILEY
DOI: 10.1038/emboj.2009.215
关键词
ERK signalling; GRK5; p-S-412-beta-arrestin1; Src family kinase; 5-HT4R
资金
- CNRS
- INSERM
- French Minister of Research
- Fondation pour la Recherche Medicale (FRM)
- ANR Blanc 2006
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
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