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


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-HT(4) receptor (5-HT(4)R)-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.

DOI: 10.1038/emboj.2009.215
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@article{Barthet2009Betaarrestin1PB, title={Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling.}, author={Ga{\"{e}l Barthet and Ga{\"{e}lle Carrat and Elizabeth Cassier and Breann L Barker and Florence Gaven and Marion Pillot and B{\'e}r{\'e}nice Framery and Lucie P Pellissier and Julie Augier and Dong Soo Kang and Sylvie Claeysen and Eric Reiter and Jean-Louis Ban{\`e}res and Jeffrey L. Benovic and Philippe Marin and J{\"{o}el Bockaert and Aline Dumuis}, journal={The EMBO journal}, year={2009}, volume={28 18}, pages={2706-18} }