Receptor sequestration in response to β-arrestin-2 phosphorylation by ERK1/2 governs steady-state levels of GPCR cell-surface expression

Proceedings of the National Academy of Sciences of the United States of America
Justine S ParadisMichel Bouvier

Abstract

MAPKs are activated in response to G protein-coupled receptor (GPCR) stimulation and play essential roles in regulating cellular processes downstream of these receptors. However, very little is known about the reciprocal effect of MAPK activation on GPCRs. To investigate possible crosstalk between the MAPK and GPCRs, we assessed the effect of ERK1/2 on the activity of several GPCR family members. We found that ERK1/2 activation leads to a reduction in the steady-state cell-surface expression of many GPCRs because of their intracellular sequestration. This subcellular redistribution resulted in a global dampening of cell responsiveness, as illustrated by reduced ligand-mediated G-protein activation and second-messenger generation as well as blunted GPCR kinases and β-arrestin recruitment. This ERK1/2-mediated regulatory process was observed for GPCRs that can interact with β-arrestins, such as type-2 vasopressin, type-1 angiotensin, and CXC type-4 chemokine receptors, but not for the prostaglandin F receptor that cannot interact with β-arrestin, implicating this scaffolding protein in the receptor's subcellular redistribution. Complementation experiments in mouse embryonic fibroblasts lacking β-arrestins combined with in vitro k...Continue Reading

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Citations

Apr 14, 2016·Proceedings of the National Academy of Sciences of the United States of America·Sophie J BradleyAndrew B Tobin
Jun 16, 2017·Molecular Biology of the Cell·Yukari Okamoto, Sojin Shikano
Jan 24, 2018·Neural Plasticity·Geehoon Chung, Sang Jeong Kim
Oct 12, 2018·Proceedings of the National Academy of Sciences of the United States of America·Franziska MendeBirgitte Holst
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Sep 2, 2021·Antioxidants & Redox Signaling·Helen WedegaertnerJoann Trejo

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