β-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling

被引:54
作者
Barthet, Gael [1 ,2 ]
Carrat, Gaelle [1 ,2 ]
Cassier, Elizabeth [1 ,2 ]
Barker, Breann [3 ]
Gaven, Florence [1 ,2 ]
Pillot, Marion [1 ,2 ]
Framery, Berenice [1 ,2 ]
Pellissier, Lucie P. [1 ,2 ]
Augier, Julie [1 ,2 ]
Kang, Dong Soo [3 ]
Claeysen, Sylvie [1 ,2 ]
Reiter, Eric [4 ,5 ,6 ]
Baneres, Jean-Louis [7 ]
Benovic, Jeffrey L. [3 ]
Marin, Philippe [1 ,2 ]
Bockaert, Joel [1 ,2 ]
Dumuis, Aline [1 ,2 ]
机构
[1] Univ Montpellier, CNRS, Inst Genom Fonct, F-34094 Montpellier 5, France
[2] INSERM, Montpellier, France
[3] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA
[4] INRA, Physiol Reprod & Comportements GMR6175, F-37380 Nouzilly, France
[5] CNRS, Nouzilly, France
[6] Univ Tours, Nouzilly, France
[7] CNRS, Inst Biomol Max Mousseron, UMR5247, Montpellier, France
关键词
ERK signalling; GRK5; p-S-412-beta-arrestin1; Src family kinase; 5-HT4R; BETA-ADRENERGIC-RECEPTOR; COUPLED-RECEPTOR; PARTIAL AGONIST; ERK ACTIVATION; ARRESTIN; KINASES; SRC; DESENSITIZATION; ENDOCYTOSIS; EXPRESSION;
D O I
10.1038/emboj.2009.215
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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
引用
收藏
页码:2706 / 2718
页数:13
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