TY - JOUR T1 - Mechanisms of Biased <em>β</em>-Arrestin-Mediated Signaling Downstream from the Cannabinoid 1 Receptor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 618 LP - 629 DO - 10.1124/mol.115.103176 VL - 89 IS - 6 AU - Francheska Delgado-Peraza AU - Kwang H. Ahn AU - Carlos Nogueras-Ortiz AU - Imran N. Mungrue AU - Ken Mackie AU - Debra A. Kendall AU - Guillermo A. Yudowski Y1 - 2016/06/01 UR - http://molpharm.aspetjournals.org/content/89/6/618.abstract N2 - 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. ER -