Sustained Gα_s signaling mediated by vasopressin type 2 receptors is ligand dependent but endocytosis and β-arrestin independent

Author(s)

Teixeira, Larissa B. ; Blouin, Marie-Jose ; Le Gouill, Christian ; Picard, Louis-Philippe ; Costa-Neto, Claudio M. ; Bouvier, Michel ; Parreiras-e-Silva, Lucas T.

• Document type: Journal article
• Source: SCIENCE SIGNALING; v. 18, n. 874, p. 14-pg., 2025-02-18.

Abstract

The canonical model of G protein-coupled receptor (GPCR) signaling comprises G protein activation at the plasma membrane, followed by receptor phosphorylation and beta-arrestin recruitment, which leads to receptor desensitization and endocytosis. However, the activation of some GPCRs results in sustained G protein signaling from intracellular compartments in a manner reportedly dependent on beta-arrestin and receptor endocytosis. The vasopressin type 2 receptor (V2R) can be activated by two structurally similar hormones, arginine vasopressin and oxytocin, both of which stimulate the production of the second messenger cyclic adenosine monophosphate (cAMP). In this study, we showed that sustained V2R signaling and endosomal G alpha s (stimulatory G protein alpha subunit) translocation could occur without beta-arrestin-mediated receptor endocytosis and was primarily controlled by the residence time of the ligand on the receptor. beta-Arrestin had opposing effects on sustained signaling: It facilitated receptor internalization into endosomes, where it activated G alpha s, and promoted cAMP production from this compartment. However, beta-arrestin-mediated receptor endocytosis also induced ligand dissociation due to the acidic endosomal environment, thereby limiting the signal. Overall, our data suggest that signals originating at the plasma membrane play a dominant role in sustained V2R signaling stimulated by arginine vasopressin. (AU)

• FAPESP's process: 16/24120-3 - Study of non-canonical roles of G proteins as new signaling mechanisms with impact on discovery and development of new drugs
• Grantee: Lucas Tabajara Parreiras e Silva
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 12/20148-0 - Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications
• Grantee: Claudio Miguel da Costa Neto
• Support Opportunities: Research Projects - Thematic Grants