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A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

Alexandre Beautrait1, Justine S Paradis2, Brandon Zimmerman3

  • 1Department of Biochemistry, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec, Canada H3T 1J4.

Nature Communications
|April 19, 2017
PubMed

Insights

Researchers developed Barbadin, a novel small molecule that selectively inhibits β-arrestin/AP2 interaction. This tool helps distinguish β-arrestin roles in G protein-coupled receptor signaling and endocytosis.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Molecular Signaling

Background:

  • G protein-coupled receptors (GPCRs) undergo desensitization and endocytosis.
  • β-arrestin recruitment to GPCRs triggers non-canonical signaling cascades.
  • Selective tools are needed to differentiate β-arrestin's roles in receptor signaling and endocytosis.

Purpose of the Study:

  • To identify a small molecule that selectively inhibits the β-arrestin/AP2 interaction.
  • To investigate the role of β-arrestin/AP2 interaction in GPCR signaling and endocytosis.

Main Methods:

  • Virtual screening and cell-based assays were employed.
  • A selective β-arrestin/β2-adaptin inhibitor, Barbadin, was identified.
  • Barbadin's effects on receptor internalization and signaling pathways were assessed.

Main Results:

  • Barbadin selectively inhibits the β-arrestin/β2-adaptin interaction without affecting receptor/β-arrestin complex formation.
  • Barbadin blocks agonist-promoted endocytosis of β2AR, V2R, and AT1R.
  • Barbadin inhibits V2R-stimulated ERK1/2 activation and blunts cAMP accumulation for V2R and β2AR.

Conclusions:

  • Barbadin is a valuable tool for dissecting β-arrestin-mediated signaling.
  • β-arrestin/AP2 interaction is crucial for endocytosis of various GPCRs.
  • β-arrestin/AP2-dependent signaling pathways contribute to both G protein-dependent and -independent signaling.

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