Daly Carole, Guseinov Akim Abdul, Hahn Hyunggu, Wright Adam, Tikhonova Irina G, Thomsen Alex Rojas Bie, Plouffe Bianca
Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
School of Pharmacy, Queen's University Belfast, Belfast, UK.
bioRxiv. 2023 Aug 21:2023.04.01.535208. doi: 10.1101/2023.04.01.535208.
The vasopressin type 2 receptor (VR) is an essential GPCR in renal regulation of water homeostasis. Upon stimulation, the VR activates Gα and Gα, which is followed by robust recruitment of β-arrestins and receptor internalization into endosomes. Unlike canonical GPCR signaling, the β-arrestin association with the VR does not terminate Gα activation, and thus, Gα-mediated signaling is sustained while the receptor is internalized. Here, we demonstrate that this VR ability to co-interact with G protein/β-arrestin and promote endosomal G protein signaling is not restricted to Gα, but also involves Gα. Furthermore, our data implies that β-arrestins potentiate Gα/Gα activation at endosomes rather than terminating their signaling. Surprisingly, we found that the VR 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.
血管加压素2型受体（VR）是肾脏调节水平衡过程中的一种重要G蛋白偶联受体（GPCR）。受到刺激后，VR会激活Gα和Gα，随后β-抑制蛋白会大量募集，受体也会内化进入内体。与典型的GPCR信号传导不同，β-抑制蛋白与VR的结合不会终止Gα的激活，因此，在受体内化时，Gα介导的信号传导仍会持续。在此，我们证明，这种VR与G蛋白/β-抑制蛋白共同相互作用并促进内体G蛋白信号传导的能力并不局限于Gα，还涉及Gα。此外，我们的数据表明，β-抑制蛋白在内体中增强了Gα/Gα的激活，而不是终止它们的信号传导。令人惊讶的是，我们发现VR在内化过程中并在较小程度上独立于β-抑制蛋白促进内体G蛋白的激活。这些新发现挑战了当前的内体GPCR信号传导模型，并表明这一过程可以通过依赖β-抑制蛋白和不依赖β-抑制蛋白的方式发生。
