title: Mechanisms of Biased β-Arrestin-Mediated Signaling Downstream from the Cannabinoid 1 Receptor.
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.
authors.affiliation: Department of Anatomy and Neurobiology (F.D.-P., G.A.Y.) and Institute of Neurobiology (F.D.-P., C.N.-O., G.A.Y.), University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (K.H.A., D.A.K.); Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (I.N.M.); and Department of Psychological & Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, Indiana (K.M.).
authors.forename: Francheska
authors.initials: F
authors.lastname: Delgado-Peraza
authors.affiliation: Department of Anatomy and Neurobiology (F.D.-P., G.A.Y.) and Institute of Neurobiology (F.D.-P., C.N.-O., G.A.Y.), University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (K.H.A., D.A.K.); Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (I.N.M.); and Department of Psychological & Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, Indiana (K.M.).
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Ahn
authors.affiliation: Department of Anatomy and Neurobiology (F.D.-P., G.A.Y.) and Institute of Neurobiology (F.D.-P., C.N.-O., G.A.Y.), University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (K.H.A., D.A.K.); Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (I.N.M.); and Department of Psychological & Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, Indiana (K.M.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Nogueras-Ortiz
authors.affiliation: Department of Anatomy and Neurobiology (F.D.-P., G.A.Y.) and Institute of Neurobiology (F.D.-P., C.N.-O., G.A.Y.), University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (K.H.A., D.A.K.); Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (I.N.M.); and Department of Psychological & Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, Indiana (K.M.).
authors.forename: Imran N
authors.initials: IN
authors.lastname: Mungrue
authors.affiliation: Department of Anatomy and Neurobiology (F.D.-P., G.A.Y.) and Institute of Neurobiology (F.D.-P., C.N.-O., G.A.Y.), University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (K.H.A., D.A.K.); Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (I.N.M.); and Department of Psychological & Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, Indiana (K.M.).
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.affiliation: Department of Anatomy and Neurobiology (F.D.-P., G.A.Y.) and Institute of Neurobiology (F.D.-P., C.N.-O., G.A.Y.), University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (K.H.A., D.A.K.); Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (I.N.M.); and Department of Psychological & Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, Indiana (K.M.).
authors.forename: Debra A
authors.initials: DA
authors.lastname: Kendall
authors.affiliation: Department of Anatomy and Neurobiology (F.D.-P., G.A.Y.) and Institute of Neurobiology (F.D.-P., C.N.-O., G.A.Y.), University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (K.H.A., D.A.K.); Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (I.N.M.); and Department of Psychological & Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, Indiana (K.M.) Guillermo.yudowski@upr.edu debra.kendall@uconn.edu.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Yudowski
mesh_terms: D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism; D005989:Glycerides / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D050505:Mutant Proteins / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D048588:Benzoxazines; D063388:Endocannabinoids; D005989:Glycerides; D009025:Morpholines; D050505:Mutant Proteins; D009281:Naphthalenes; D020033:Protein Isoforms; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D000071557:beta-Arrestins; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; D011494:Protein Kinases; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6