Mechanisms of Biased β-Arrestin-Mediated Signaling Downstream from the Cannabinoid 1 Receptor

Activation of G protein-coupled receptors results in multiple waves of signaling that are mediated by heterotrimeric G proteins and the scaffolding proteins β-arrestin 1/2. Ligands can elicit full or subsets of cellular responses, a concept defined as ligand bias or functional selectivity. However,...

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Bibliographic Details
Published in:Molecular pharmacology 2016-06, Vol.89 (6), p.618-629
Main Authors: Delgado-Peraza, Francheska, Ahn, Kwang H., Nogueras-Ortiz, Carlos, Mungrue, Imran N., Mackie, Ken, Kendall, Debra A., Yudowski, Guillermo A.
Format: Article
Language:English
Subjects:
Arachidonic Acids - pharmacology
Benzoxazines - pharmacology
beta-Arrestins - metabolism
Endocannabinoids - pharmacology
G-Protein-Coupled Receptor Kinases - metabolism
Glycerides - pharmacology
HEK293 Cells
Humans
Morpholines - pharmacology
Mutant Proteins - metabolism
Naphthalenes - pharmacology
Protein Binding - drug effects
Protein Isoforms - metabolism
Protein Kinases - metabolism
Receptor, Cannabinoid, CB1 - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Signal Transduction - drug effects
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Summary:Activation of G protein-coupled receptors results in multiple waves of signaling that are mediated by heterotrimeric G proteins and the scaffolding proteins β-arrestin 1/2. Ligands can elicit full or subsets of cellular responses, a concept defined as ligand bias or functional selectivity. However, our current understanding of β-arrestin-mediated signaling is still very limited. Here we provide a comprehensive view of β-arrestin-mediated signaling from the cannabinoid 1 receptor (CB1R). By using a signaling biased receptor, we define the cascades, specific receptor kinases, and molecular mechanism underlying β-arrestin-mediated signaling: We identify the interaction kinetics of CB1R and β-arrestin 1 during their endocytic trafficking as directly proportional to its efficacy. Finally, we demonstrate that signaling results in the control of genes clustered around prosurvival and proapoptotic functions among others. Together, these studies constitute a comprehensive description of β-arrestin-mediated signaling from CB1Rs and suggest modulation of receptor endocytic trafficking as a therapeutic approach to control β-arrestin-mediated signaling.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.115.103176