β-Arrestin-dependent and -independent endosomal G protein activation by the vasopressin type 2 receptor.

The vasopressin type 2 receptor (V ₂ R) is an essential G protein-coupled receptor (GPCR) in renal regulation of water homeostasis. Upon stimulation, the V ₂ R activates Gα _s and Gα _q/11 , which is followed by robust recruitment of β-arrestins and receptor internalization into endosomes. Unlike canonical GPCR signaling, the β-arrestin association with the V ₂ R does not terminate Gα _s activation, and thus, Gα _s -mediated signaling is sustained while the receptor is internalized. Here, we demonstrate that this V ₂ R ability to co-interact with G protein/β-arrestin and promote endosomal G protein signaling is not restricted to Gα _s , but also involves Gα _q/11 . Furthermore, our data imply that β-arrestins potentiate Gα _s /Gα _q/11 activation at endosomes rather than terminating their signaling. Surprisingly, we found that the V ₂ R internalizes and promote endosomal G protein activation independent of β-arrestins to a minor degree. These new observations challenge the current model of endosomal GPCR signaling and suggest that this event can occur in both β-arrestin-dependent and -independent manners.
Competing Interests: CD, AG, HH, AW, IT, AT, BP No competing interests declared
(© 2023, Daly et al.)