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Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling
β-Arrestins are master regulators of cellular signaling that operate by desensitizing ligand-activated G-protein-coupled receptors (GPCRs) at the plasma membrane and promoting their subsequent endocytosis. The endocytic activity of β-arrestins is ligand dependent, triggered by GPCR binding, and incr...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9681205/ https://www.ncbi.nlm.nih.gov/pubmed/36250629 http://dx.doi.org/10.7554/eLife.81563 |
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author | Barsi-Rhyne, Benjamin Manglik, Aashish von Zastrow, Mark |
author_facet | Barsi-Rhyne, Benjamin Manglik, Aashish von Zastrow, Mark |
author_sort | Barsi-Rhyne, Benjamin |
collection | PubMed |
description | β-Arrestins are master regulators of cellular signaling that operate by desensitizing ligand-activated G-protein-coupled receptors (GPCRs) at the plasma membrane and promoting their subsequent endocytosis. The endocytic activity of β-arrestins is ligand dependent, triggered by GPCR binding, and increasingly recognized to have a multitude of downstream signaling and trafficking consequences that are specifically programmed by the bound GPCR. However, only one biochemical ‘mode’ for GPCR-mediated triggering of the endocytic activity is presently known – displacement of the β-arrestin C-terminus (CT) to expose clathrin-coated pit-binding determinants that are masked in the inactive state. Here, we revise this view by uncovering a second mode of GPCR-triggered endocytic activity that is independent of the β-arrestin CT and, instead, requires the cytosolic base of the β-arrestin C-lobe (CLB). We further show each of the discrete endocytic modes is triggered in a receptor-specific manner, with GPCRs that bind β-arrestin transiently (‘class A’) primarily triggering the CLB-dependent mode and GPCRs that bind more stably (‘class B’) triggering both the CT and CLB-dependent modes in combination. Moreover, we show that different modes have opposing effects on the net signaling output of receptors – with the CLB-dependent mode promoting rapid signal desensitization and the CT-dependent mode enabling prolonged signaling. Together, these results fundamentally revise understanding of how β-arrestins operate as efficient endocytic adaptors while facilitating diversity and flexibility in the control of cell signaling. |
format | Online Article Text |
id | pubmed-9681205 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-96812052022-11-23 Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling Barsi-Rhyne, Benjamin Manglik, Aashish von Zastrow, Mark eLife Cell Biology β-Arrestins are master regulators of cellular signaling that operate by desensitizing ligand-activated G-protein-coupled receptors (GPCRs) at the plasma membrane and promoting their subsequent endocytosis. The endocytic activity of β-arrestins is ligand dependent, triggered by GPCR binding, and increasingly recognized to have a multitude of downstream signaling and trafficking consequences that are specifically programmed by the bound GPCR. However, only one biochemical ‘mode’ for GPCR-mediated triggering of the endocytic activity is presently known – displacement of the β-arrestin C-terminus (CT) to expose clathrin-coated pit-binding determinants that are masked in the inactive state. Here, we revise this view by uncovering a second mode of GPCR-triggered endocytic activity that is independent of the β-arrestin CT and, instead, requires the cytosolic base of the β-arrestin C-lobe (CLB). We further show each of the discrete endocytic modes is triggered in a receptor-specific manner, with GPCRs that bind β-arrestin transiently (‘class A’) primarily triggering the CLB-dependent mode and GPCRs that bind more stably (‘class B’) triggering both the CT and CLB-dependent modes in combination. Moreover, we show that different modes have opposing effects on the net signaling output of receptors – with the CLB-dependent mode promoting rapid signal desensitization and the CT-dependent mode enabling prolonged signaling. Together, these results fundamentally revise understanding of how β-arrestins operate as efficient endocytic adaptors while facilitating diversity and flexibility in the control of cell signaling. eLife Sciences Publications, Ltd 2022-10-17 /pmc/articles/PMC9681205/ /pubmed/36250629 http://dx.doi.org/10.7554/eLife.81563 Text en © 2022, Barsi-Rhyne et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Barsi-Rhyne, Benjamin Manglik, Aashish von Zastrow, Mark Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling |
title | Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling |
title_full | Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling |
title_fullStr | Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling |
title_full_unstemmed | Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling |
title_short | Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling |
title_sort | discrete gpcr-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9681205/ https://www.ncbi.nlm.nih.gov/pubmed/36250629 http://dx.doi.org/10.7554/eLife.81563 |
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