Related Experiment Video

Updated: Jan 8, 2026

Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
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Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay

Published on: March 10, 2020

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Multi-faceted roles of β-arrestins in G protein-coupled receptor endocytosis

Junke Liu1, Li Xue1,2, Magalie A Ravier1

  • 1Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.

Nature Communications
|December 11, 2025
PubMed

Insights

G protein-coupled receptors (GPCRs) internalization varies; β-arrestins (βarrs) are essential for only a third of GPCRs. Glucagon-like peptide-1 receptor (GLP-1R) uses βarr-independent pathways, highlighting diverse receptor regulation mechanisms.

Area of Science:

  • Cell Biology
  • Molecular Pharmacology
  • Biochemistry

Background:

  • G protein-coupled receptors (GPCRs) cell surface activity is regulated by internalization.
  • GPCR internalization is linked to disease and often involves β-arrestins (βarrs).
  • The role of βarrs in GPCR internalization is not fully understood for all receptors.

Purpose of the Study:

  • To investigate the necessity of β-arrestins (βarrs) for the internalization of 60 different GPCRs.
  • To elucidate the molecular mechanism of glucagon-like peptide-1 receptor (GLP-1R) internalization.
  • To explore alternative internalization pathways for GPCRs.

Main Methods:

  • Screening of β-arrestin dependency for agonist-induced internalization across 60 GPCRs.
  • Development of Förster resonance energy transfer (FRET)-based assays to study molecular interactions.
  • Analysis of GLP-1R internalization mechanisms, focusing on β-arrestin and clathrin adaptor protein complex-2 interactions.

Main Results:

  • β-arrestins are essential for agonist-induced internalization in only one-third of the studied GPCRs.
  • Half of the GPCRs showed partial or no β-arrestin dependency for endocytosis.
  • GLP-1R primarily internalizes via a β-arrestin-independent pathway involving direct binding of clathrin adaptor protein complex-2.
  • GLP-1R internalization shifts to a β-arrestin-dependent mechanism when the clathrin adaptor protein complex-2 pathway is impaired.

Conclusions:

  • GPCR internalization is regulated by multiple, diverse mechanisms, not solely β-arrestin recruitment.
  • The glucagon-like peptide-1 receptor (GLP-1R) utilizes distinct internalization pathways.
  • Understanding these varied mechanisms offers new strategies for controlling GPCR signaling.

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