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- Title
β-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT<sub>4</sub> receptor signalling.
- Authors
Barthet, Gaël; Carrat, Gaëlle; Cassier, Elizabeth; Barker, Breann; Gaven, Florence; Pillot, Marion; Framery, Bérénice; Pellissier, Lucie P.; Augier, Julie; Dong Soo Kang; Claeysen, Sylvie; Reiter, Eric; Banères, Jean-Louis; Benovic, Jeffrey L.; Marin, Philippe; Bockaert, Joël; Dumuis, Aline
- Abstract
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 Gs 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 β–arrestin1 to a phosphorylated serine/threonine cluster located within the receptor C-t domain and the phosphorylation, by GRK5, of β–arrestin1 (at Ser412) bound to the receptor. Phosphorylated β-arrestin1 in turn prevented activation of Src constitutively bound to 5-HT4Rs, a necessary step in receptor-stimulated ERK signalling. This is the first demonstration that β-arrestin1 phosphorylation by GRK5 regulates G protein-independent signalling.
- Subjects
PHOSPHORYLATION; PROTEINS; NEURONS; EMBRYONIC stem cells; KIDNEYS
- Publication
EMBO Journal, 2009, Vol 28, Issue 18, p2706
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/emboj.2009.215