2. Academic Validation
  3. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

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

  • Nat Commun. 2017 Apr 18;8:15054. doi: 10.1038/ncomms15054.
Alexandre Beautrait 1,  Justine S Paradis 2,  Brandon Zimmerman 3,  Jenna Giubilaro 3,  Ljiljana Nikolajev 4,  Sylvain Armando 4,  Hiroyuki Kobayashi 1,  Lama Yamani 4,  Yoon Namkung 4,  Franziska M Heydenreich 5,  Etienne Khoury 4,  Martin Audet 1,  Philippe P Roux 6,  Dmitry B Veprintsev 5,  Stéphane A Laporte 3 4 7,  Michel Bouvier 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec, Canada H3T 1J4.
  • 2 Department of Molecular Biology Program, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec, Canada H3T 1J4.
  • 3 Department of Pharmacology and Therapeutics, Research Institute of McGill University Health Centre (RI-MUHC), McGill University, Montréal, Quebec, Canada H4A 3J1.
  • 4 Department of Medicine, Research Institute of McGill University Health Centre (RI-MUHC), McGill University, Montréal, Quebec, Canada H4A 3J1.
  • 5 Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut,5232 Villigen PSI, Switzerland, Switzerland.
  • 6 Department of Pathology and Cellular Biology, Institute of Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Quebec, Canada H3T 1J4.
  • 7 Department of Anatomy and Cell Biology, Research Institute of McGill University Health Centre (RI-MUHC), McGill University, Montréal, Quebec, Canada H4A 3J1.
PMID: 28416805 DOI: 10.1038/ncomms15054
Abstract

In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-119706
    98.93%, β-arrestin/β2-adaptin Interaction Inhibitor