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

Gaël Barthet1, Gaëlle Carrat, Elizabeth Cassier

  • 1Institut de Génomique Fonctionnelle, Universités de Montpellier, CNRS, Montpellier, France.

The EMBO Journal
|August 8, 2009
PubMed

Insights

GPCR kinase 5 (GRK5) inhibits G protein-independent signaling via the 5-HT(4) receptor. This involves beta-arrestin1 phosphorylation, preventing Src/ERK pathway activation and offering insights into G protein-independent pathway regulation.

Area of Science:

  • Cellular signaling pathways
  • Molecular and cellular pharmacology
  • Neuroscience

Background:

  • G protein-coupled receptors (GPCRs) can activate G protein-independent signaling pathways.
  • The mechanisms regulating these G protein-independent pathways, particularly desensitization, are not well understood.

Purpose of the Study:

  • To investigate the regulation and desensitization of the G protein-independent 5-HT(4) receptor (5-HT(4)R)-operated Src/ERK pathway.
  • To elucidate the role of GPCR kinase 5 (GRK5) in this process.

Main Methods:

  • Utilized human embryonic kidney (HEK)-293 cells and colliculi neurons.
  • Investigated the physical association of GRK5 with the 5-HT(4)R C-terminus.
  • Examined the phosphorylation of beta-arrestin1 and its impact on Src/ERK signaling.

Main Results:

  • GRK5 physically associates with the 5-HT(4)R C-terminus and inhibits the G protein-independent Src/ERK pathway.
  • Inhibition requires beta-arrestin1 association with a phosphorylated C-terminal cluster and subsequent GRK5-mediated phosphorylation of beta-arrestin1.
  • Phosphorylated beta-arrestin1 prevents Src activation, thereby blocking ERK signaling.

Conclusions:

  • This study demonstrates that beta-arrestin1 phosphorylation by GRK5 is a key mechanism for regulating G protein-independent signaling.
  • Provides the first evidence of beta-arrestin1 phosphorylation by GRK5 controlling G protein-independent pathways.

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