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

Alexandre Beautrait, Justine S. Paradis, Brandon Zimmerman, Jenna Giubilaro, Ljiljana Nikolajev, Sylvain Armando, Hiroyuki Kobayashi, Lama Yamani, Yoon Namkung, Franziska M. Heydenreich, Etienne Khoury, Martin Audet, Philippe P. Roux, Dmitry B. Veprintsev, Stéphane A. Laporte () and Michel Bouvier ()
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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
Michel Bouvier: Institute for Research in Immunology and Cancer (IRIC), Université de Montréal

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15054

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