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Mol Biol Cell. 2017 Nov 15;28(24):3554-3561. doi: 10.1091/mbc.E17-03-0198. Epub 2017 Sep 27.

Retromer stops beta-arrestin 1-mediated signaling from internalized cannabinoid 2 receptors.

Author information

1
Institute of Neurobiology, University of Puerto Rico, San Juan, PR 00901.
2
Department of Physiology and Biophysics, University of Puerto Rico, Medical San Juan, PR 00936.
3
Department of Anatomy and Neurobiology, University of Puerto Rico, Medical San Juan, PR 00936.
4
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092.
5
Institute of Neurobiology, University of Puerto Rico, San Juan, PR 00901 guillermo.yudowski@upr.edu.

Abstract

G protein-coupled receptors mediate their complex functions through activation of signaling cascades from receptors localized at the cell surface and endosomal compartments. These signaling pathways are modulated by heterotrimeric G proteins and the scaffold proteins beta-arrestin 1 and 2. However, in contrast to the events occurring at the cell surface, our knowledge of the mechanisms controlling signaling from receptors localized at intracellular compartments is still very limited. Here we sought to investigate the intracellular signaling from cannabinoid 2 receptor (CB2R). First, we show that receptor internalization is required for agonist-induced phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Then we demonstrate that ERK1/2 activation is mediated by beta-arrestin 1 from receptors localized exclusively at Rab4/5 compartments. Finally, we identify the retromer complex as a gatekeeper, terminating beta-arrestin 1-mediated ERK phosphorylation. These findings extend our understanding of the events controlling signaling from endocytosed receptors and identify the retromer as a modulator of beta-arrestin-mediated signaling from CB2R.

PMID:
28954865
PMCID:
PMC5683765
DOI:
10.1091/mbc.E17-03-0198
[Indexed for MEDLINE]
Free PMC Article

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