title: Ligand-specific endocytic dwell times control functional selectivity of the cannabinoid receptor 1.
abstract: G protein-coupled receptors (GPCRs) are the major transducers of external stimuli and key therapeutic targets in many pathological conditions. When activated by different ligands, one receptor can elicit multiple signalling cascades that are mediated by G proteins or β-arrestin, a process defined as functional selectivity or ligand bias. However, the dynamic mechanisms underlying β-arrestin signalling remain unknown. Here by studying the cannabinoid receptor 1 (CB1R), we identify ligand-specific endocytic dwell times, that is, the time during which receptors are clustered into clathrin pits together with β-arrestins before endocytosis, as the mechanism controlling β-arrestin signalling. Agonists inducing short endocytic dwell times produce little or no β-arrestin signalling, whereas those eliciting prolonged dwell times induce robust signalling. Remarkably, extending CB1R dwell times by preventing endocytosis substantially increased β-arrestin signalling. These studies reveal how receptor activation translates into β-arrestin signalling and identify a mechanism to control this pathway.
authors.affiliation: 1] Department of Anatomy and Neurobiology, University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan 00936, Puerto Rico [2].
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Flores-Otero
authors.affiliation: 1] Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA [2].
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Ahn
authors.affiliation: 1] Department of Anatomy and Neurobiology, University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan 00936, Puerto Rico [2] Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, 201 Boulevard del Valle, San Juan 00901, Puerto Rico.
authors.forename: Francheska
authors.initials: F
authors.lastname: Delgado-Peraza
authors.affiliation: Department of Psychological and Brain Sciences, Gill Center for Biomedical Sciences, Indiana University, Bloomington, Indiana 47405, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Kendall
authors.affiliation: 1] Department of Anatomy and Neurobiology, University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan 00936, Puerto Rico [2] Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, 201 Boulevard del Valle, San Juan 00901, Puerto Rico.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Yudowski
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D048588:Benzoxazines / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002966:Clathrin / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D063388:Endocannabinoids / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D005989:Glycerides / Q000494:pharmacology; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D001095:Arachidonic Acids; D019390:Arrestins; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002966:Clathrin; D063388:Endocannabinoids; D005989:Glycerides; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D034741:RNA, Small Interfering; 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
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