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A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling
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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399295/ https://www.ncbi.nlm.nih.gov/pubmed/28416805 http://dx.doi.org/10.1038/ncomms15054 |
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author | Beautrait, Alexandre Paradis, Justine S. Zimmerman, Brandon Giubilaro, Jenna Nikolajev, Ljiljana Armando, Sylvain Kobayashi, Hiroyuki Yamani, Lama Namkung, Yoon Heydenreich, Franziska M. Khoury, Etienne Audet, Martin Roux, Philippe P. Veprintsev, Dmitry B. Laporte, Stéphane A. Bouvier, Michel |
author_facet | Beautrait, Alexandre Paradis, Justine S. Zimmerman, Brandon Giubilaro, Jenna Nikolajev, Ljiljana Armando, Sylvain Kobayashi, Hiroyuki Yamani, Lama Namkung, Yoon Heydenreich, Franziska M. Khoury, Etienne Audet, Martin Roux, Philippe P. Veprintsev, Dmitry B. Laporte, Stéphane A. Bouvier, Michel |
author_sort | Beautrait, Alexandre |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5399295 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53992952017-05-12 A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling Beautrait, Alexandre Paradis, Justine S. Zimmerman, Brandon Giubilaro, Jenna Nikolajev, Ljiljana Armando, Sylvain Kobayashi, Hiroyuki Yamani, Lama Namkung, Yoon Heydenreich, Franziska M. Khoury, Etienne Audet, Martin Roux, Philippe P. Veprintsev, Dmitry B. Laporte, Stéphane A. Bouvier, Michel Nat Commun Article 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. Nature Publishing Group 2017-04-18 /pmc/articles/PMC5399295/ /pubmed/28416805 http://dx.doi.org/10.1038/ncomms15054 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Beautrait, Alexandre Paradis, Justine S. Zimmerman, Brandon Giubilaro, Jenna Nikolajev, Ljiljana Armando, Sylvain Kobayashi, Hiroyuki Yamani, Lama Namkung, Yoon Heydenreich, Franziska M. Khoury, Etienne Audet, Martin Roux, Philippe P. Veprintsev, Dmitry B. Laporte, Stéphane A. Bouvier, Michel A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling |
title | A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling |
title_full | A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling |
title_fullStr | A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling |
title_full_unstemmed | A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling |
title_short | A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling |
title_sort | new inhibitor of the β-arrestin/ap2 endocytic complex reveals interplay between gpcr internalization and signalling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399295/ https://www.ncbi.nlm.nih.gov/pubmed/28416805 http://dx.doi.org/10.1038/ncomms15054 |
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