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

The vasopressin type 2 receptor (V2R) is an essential G protein-coupled receptor (GPCR) in renal regulation of water homeostasis. Upon stimulation, the V2R activates G alpha(s) and G alpha(q/11), which is followed by robust recruitment of beta-arrestins and receptor internalization into endosomes. Unlike canonical GPCR signaling, the beta-arrestin association with the V2R does not terminate G alpha(s) activation, and thus, G alpha(s)-mediated signaling is sustained while the receptor is internalized. Here, we demonstrate that this V2R ability to co-interact with G protein/beta-arrestin and promote endosomal G protein signaling is not restricted to G alpha(s), but also involves G alpha(q/11). Furthermore, our data imply that beta-arrestins potentiate G alpha(s)/G alpha(q/11) activation at endosomes rather than terminating their signaling. Surprisingly, we found that the V2R internalizes and promote endosomal G protein activation independent of beta-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 beta-arrestin-dependent and -independent manners.