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
  • 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.

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