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

Gaël Barthet, Gaëlle Carrat, Elizabeth Cassier, Breann Barker, Florence Gaven, Marion Pillot, Bérénice Framery, Lucie P Pellissier, Julie Augier, Dong Soo Kang, Sylvie Claeysen, Eric Reiter, Jean-Louis Banères, Jeffrey L Benovic, Philippe Marin, Joël Bockaert, Aline Dumuis
EMBO J. 2009-08-06; 28(18): 2706-2718
DOI: 10.1038/emboj.2009.215

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Barthet G(1), Carrat G, Cassier E, Barker B, Gaven F, Pillot M, Framery B, Pellissier LP, Augier J, Kang DS, Claeysen S, Reiter E, Banères JL, Benovic JL, Marin P, Bockaert J, Dumuis A.

Author information:
(1)Institut de Génomique Fonctionnelle, Universités de Montpellier, CNRS, Montpellier, France.

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.

 

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