期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15054
关键词
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资金
- Groupe de Recherche Universitaire sur le Medicament (GRUM)
- Fonds de la Recherche du Quebec - Sante (FRQS)
- Canadian Institutes of Health Research (CIHR)
- McGill Division of Endocrinology and Metabolism
- UdeM faculte des etudes superieures et postdoctorales
- CIHR [MOP-10501, MOP-74603, MOP-123408]
- FRQS
In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, beta-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of beta-arrestin recruitment to the receptor and beta-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 beta-arrestin and the beta 2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/beta-arrestin complexes. This selective beta-arrestin/beta 2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical beta 2-adrenergic (beta 2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect beta-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 beta 2AR, supporting the concept of beta-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.
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