Dataset Information

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

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-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.

SUBMITTER: Barthet G

PROVIDER: S-EPMC2750015 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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

Barthet Gaël G Carrat Gaëlle G Cassier Elizabeth E Barker Breann B Gaven Florence F Pillot Marion M Framery Bérénice B Pellissier Lucie P LP Augier Julie J Kang Dong Soo DS Claeysen Sylvie S Reiter Eric E Banères Jean-Louis JL Benovic Jeffrey L JL Marin Philippe P Bockaert Joël J Dumuis Aline A

The EMBO journal 20090806 18

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 hum ...[more]

PMID: 19661922

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Project description:Muscle may experience hypoglycaemia during ischaemia or insulin infusion. During severe hypoglycaemia energy production is blocked, and an increase of AMP:ATP activates the energy sensor and putative insulin-sensitiser AMP-activated protein kinase (AMPK). AMPK promotes energy conservation and survival by shutting down anabolism and activating catabolic pathways. We investigated the molecular mechanism of a unique glucose stress defence pathway involving AMPK-dependent, insulin-independent activation of the insulin signalling pathway.Cardiac or skeletal myocytes were subjected to glucose and insulin-free incubation for increasing intervals up to 20 h. AMPK, and components of the insulin signalling pathway and their targets were quantified by western blot using phosphor-specific antibodies. Phosphomimetics were used to determine the function of IRS-1 Ser789 phosphorylation and in vitro [³²P]ATP kinase assays were used to measure the phosphorylation of the purified insulin receptor by AMPK.Glucose deprivation increased Akt-Thr308 and Akt-Ser473 phosphorylation by almost tenfold. Phosphorylation of glycogen synthase kinase 3 beta increased in parallel, but phosphorylation of ribosomal 70S subunit-S6 protein kinase and mammalian target of rapamycin decreased. AMPK inhibitors blocked and aminoimidazole carboxamide ribonucleotide (AICAR) mimicked the effects of glucose starvation. Glucose deprivation increased the phosphorylation of IRS-1 on serine-789, but phosphomimetics revealed that this conferred negative regulation. Glucose deprivation enhanced tyrosine phosphorylation of IRS-1 and the insulin receptor, effects that were blocked by AMPK inhibition and mimicked by AICAR. In vitro kinase assays using purified proteins confirmed that the insulin receptor is a direct target of AMPK.AMPK phosphorylates and activates the insulin receptor, providing a direct link between AMPK and the insulin signalling pathway; this pathway promotes energy conservation and survival of muscle exposed to severe glucose deprivation.

Dataset Information

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

Publications

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

Similar Datasets

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