β-arrestin-dependent and -independent endosomal G protein activation by the vasopressin type 2 receptor.
β-arrestin-dependent and -independent endosomal G protein activation by the vasopressin type 2 receptor.
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β-arrestin 依赖和独立的内体 G 蛋白由加压素 2 型受体激活。
DOI：
10.1101/2023.04.01.535208
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Plouffe,Bianca
中科院分区：
文献类型：
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作者：
Daly,Carole;Guseinov,AkimAbdul;Hahn,Hyunggu;Wright,Adam;Tikhonova,IrinaG;Thomsen,AlexRojasBie;Plouffe,Bianca
抗利尿激素2型受体（v2r）是肾脏水稳态调节中必需的G蛋白偶联受体（GPCR）。受到刺激后，v2r激活Gα s和Gα q/11，随后β-阻滞蛋白的大量募集和受体内化进入内体。与典型的GPCR信号传导不同，β-阻滞蛋白与v2r的结合不会终止Gα s的激活，因此，当受体内化时，Gα s介导的信号传导是持续的。在这里，我们证明了这种v2r与G蛋白/β-阻滞蛋白共作用并促进内体G蛋白信号传导的能力不仅限于Gα s，而且还涉及Gα q/11。此外，我们的数据表明β-阻滞蛋白增强了内体上Gα s/Gα q/11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v2r内化并促进内体G蛋白的激活，在较小程度上独立于β-阻滞蛋白。这些新的观察结果挑战了当前的内体GPCR信号传导模型，并表明该事件可能以β-抑制蛋白依赖和独立的方式发生。
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.