PDF(Pubmed)
Abstract：
Classically, G protein-coupled receptors (GPCRs) promote signaling at the plasma membrane through activation of heterotrimeric Gαβγ proteins, followed by the recruitment of GPCR kinases and βarrestin (βarr) to initiate receptor desensitization and internalization. However, studies demonstrated that some GPCRs continue to signal from internalized compartments, with distinct cellular responses. Both βarr and Gβγ contribute to such non-canonical endosomal G protein signaling, but their specific roles and contributions remain poorly understood. Here, we demonstrate that the vasopressin V2 receptor (V2R)-βarr complex scaffolds Gβγ at the plasma membrane through a direct interaction with βarr, enabling its transport to endosomes. Gβγ subsequently potentiates Gαs endosomal translocation, presumably to regenerate an endosomal pool of heterotrimeric Gs. This work shines light on the mechanism underlying G protein subunits translocation from the plasma membrane to the endosomes and provides a basis for understanding the role of βarr in mediating sustained G protein signaling.
摘要：
经典的,G蛋白偶联受体（GPCRs）通过激活异源三聚体Gαβγ蛋白促进质膜信号传导，随后招募GPCR激酶和βarrestin（βarr）以启动受体脱敏和内化。然而,研究表明，一些GPCRs继续从内化的隔室发出信号，具有不同的细胞反应。βarr和Gβγ都有助于这种非经典内体G蛋白信号传导，但是他们的具体角色和贡献仍然知之甚少。这里,我们证明了加压素V2受体（V2R）-βarr复合物通过与βarr的直接相互作用在质膜上支架Gβγ，使其能够运输到内体。Gβγ随后增强Gαs内体易位，可能会再生异源三聚体Gs的内体库。这项工作揭示了G蛋白亚基从质膜转位到内体的潜在机制，并为理解βarr在介导持续G蛋白信号传导中的作用提供了基础。
