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

Author

Listed:
  • Alexandre Beautrait

    (Institute for Research in Immunology and Cancer (IRIC), Université de Montréal)

  • Justine S. Paradis

    (Institute for Research in Immunology and Cancer (IRIC), Université de Montréal)

  • Brandon Zimmerman

    (Research Institute of McGill University Health Centre (RI-MUHC), McGill University)

  • Jenna Giubilaro

    (Research Institute of McGill University Health Centre (RI-MUHC), McGill University)

  • Ljiljana Nikolajev

    (Research Institute of McGill University Health Centre (RI-MUHC), McGill University)

  • Sylvain Armando

    (Research Institute of McGill University Health Centre (RI-MUHC), McGill University)

  • Hiroyuki Kobayashi

    (Institute for Research in Immunology and Cancer (IRIC), Université de Montréal)

  • Lama Yamani

    (Research Institute of McGill University Health Centre (RI-MUHC), McGill University)

  • Yoon Namkung

    (Research Institute of McGill University Health Centre (RI-MUHC), McGill University)

  • Franziska M. Heydenreich

    (Laboratory of Biomolecular Research, Paul Scherrer Institut,5232 Villigen PSI, Switzerland, Switzerland)

  • Etienne Khoury

    (Research Institute of McGill University Health Centre (RI-MUHC), McGill University)

  • Martin Audet

    (Institute for Research in Immunology and Cancer (IRIC), Université de Montréal)

  • Philippe P. Roux

    (Institute of Research in Immunology and Cancer (IRIC), Université de Montréal)

  • Dmitry B. Veprintsev

    (Laboratory of Biomolecular Research, Paul Scherrer Institut,5232 Villigen PSI, Switzerland, Switzerland)

  • Stéphane A. Laporte

    (Research Institute of McGill University Health Centre (RI-MUHC), McGill University
    Research Institute of McGill University Health Centre (RI-MUHC), McGill University
    Research Institute of McGill University Health Centre (RI-MUHC), McGill University)

  • Michel Bouvier

    (Institute for Research in Immunology and Cancer (IRIC), Université de Montréal)

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.

Suggested Citation

  • Alexandre Beautrait & Justine S. Paradis & Brandon Zimmerman & Jenna Giubilaro & Ljiljana Nikolajev & Sylvain Armando & Hiroyuki Kobayashi & Lama Yamani & Yoon Namkung & Franziska M. Heydenreich & Eti, 2017. "A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling," Nature Communications, Nature, vol. 8(1), pages 1-16, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15054
    DOI: 10.1038/ncomms15054
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