V 1b vasopressin receptor trafficking and signaling: Role of arrestins, G proteins and Src kinase

• Published in: Traffic (Copenhagen, Denmark) Vol. 19; no. 1; pp. 58 - 82
• Main Authors: Perkovska, Sanja, Méjean, Catherine, Ayoub, Mohammed Akli, Li, Juan, Hemery, Floriane, Corbani, Maithé, Laguette, Nadine, Ventura, Maria-Angeles, Orcel, Hélène, Durroux, Thierry, Mouillac, Bernard, Mendre, Christiane
• Format: Journal Article
• Language: English
• Published: England 01.01.2018
• Subjects: Animals; beta-Arrestins - chemistry; beta-Arrestins - metabolism; Binding Sites; GTP-Binding Proteins - metabolism; HEK293 Cells; Humans; MAP Kinase Signaling System; Mice; Protein Binding; Protein Transport; Receptors, Vasopressin - metabolism; src-Family Kinases - metabolism; BRET; V1b and V2 vasopressin receptors; signal transduction; mitogen-activated protein kinase (MAPK); Src kinase; intracellular trafficking; FRET; G-protein-coupled receptor (GPCR); arrestin; biased signaling; DERET
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12535

The signaling pathway of G protein-coupled receptors is strongly linked to their trafficking profile. Little is known about the molecular mechanisms involved in the vasopressin receptor V subtype (V R) trafficking and its impact on receptor signaling and regulation. For this purpose, we investigated the role of β-arrestins in receptor desensitization, internalization and recycling and attempted to dissect the V R-mediated MAP kinase pathway. Using MEF cells Knocked-out for β-arrestins 1 and 2, we demonstrated that both β-arrestins 1 and 2 play a fundamental role in internalization and recycling of V R with a rapid and transient V R-β-arrestin interaction in contrast to a slow and long-lasting β-arrestin recruitment of the V vasopressin receptor subtype (V R). Using V R-V R chimeras and V R C-terminus truncations, we demonstrated the critical role of the V R C-terminus in its interaction with β-arrestins thereby regulating the receptor internalization and recycling kinetics in a phosphorylation-independent manner. In parallel, V R MAP kinase activation was dependent on arrestins and Src-kinase but independent on G proteins. Interestingly, Src interacted with hV R at basal state and dissociated when receptor internalization occurred. Altogether, our data describe for the first time the trafficking profile and MAP kinase pathway of V R involving both arrestins and Src kinase family.