Abstract
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.
Footnotes
- Received December 28, 2015.
- Accepted March 22, 2016.
This work was supported by research grants from the National Institutes of Health National Institute of Drug Abuse to G.A.Y. and C.N.O. [Grants DA023444 and R01DA037924]; National Institute of Minority Health and Health Disparities to G.A.Y and F.D.P. [Grants NIMHD 8G12-MD007600], and from the National Science Foundation [DBI 0115825]; D.A.K. was supported by the National Institute of Drug Abuse [Grant DA020763]; I.N.M was supported by the National Heart, Lung, and Blood Institute [Grants HL094709 and P30GM106392] and the National Science Foundation [Grant 1359140]; K.M. was supported by the National Institute of Drug Abuse [Grants DA011322 and DA021696]. G.A.Y. received further support from the Puerto Rico Science Trust.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2016 The Author(s)
This is an open access article distributed under the CC BY-NC Attribution 4.0 International license.