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bioRxiv · 10.1101/2023.04.01.535208

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

Daly, C.·Guseinov, A. A.·Hahn, H.·Tikhonova, I.·Thomsen, A. R. B.·Plouffe, B.
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Abstract

The vasopressin type 2 receptor (V2R) is an essential GPCR in renal regulation of water homeostasis. Upon stimulation, the V2R activates Gs and Gq/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 Gs activation, and thus, Gs-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 Gs, but also involves Gq/11. Furthermore, our data implies that {beta}-arrestins potentiate Gs/Gq/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. IMPACT STATEMENTThe vasopressin type 2 receptor promotes dual Gs and Gq/11 signaling at early endosomes in {beta}-arrestin-dependent and -independent manners.

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Daly, C., Guseinov, A. A., Hahn, H., Tikhonova, I., Thomsen, A. R. B., Plouffe, B.. 2023-04-02. β-arrestin-dependent and -independent endosomal G protein activation by the vasopressin type 2 receptor. https://doi.org/10.1101/2023.04.01.535208

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