Department of Biochemistry and Molecular Medicine, University of Montreal, Montreal, QC, H3T 1J4, Canada.
Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, H3T 1J4, Canada.
Commun Biol. 2024 Jul 7;7(1):826. doi: 10.1038/s42003-024-06512-y.
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 V receptor (VR)-βarr complex scaffolds Gβγ at the plasma membrane through a direct interaction with βarr, enabling its transport to endosomes. Gβγ subsequently potentiates Gα endosomal translocation, presumably to regenerate an endosomal pool of heterotrimeric G. 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.
经典理论认为，G 蛋白偶联受体（GPCR）通过激活异三聚体 Gαβγ 蛋白在质膜上促进信号转导，随后 GPCR 激酶和β-arrestin（βarr）募集以启动受体脱敏和内化。然而，研究表明，一些 GPCR 继续从内化的隔室中发出信号，产生不同的细胞反应。βarr 和 Gβγ 都有助于这种非经典的内体 G 蛋白信号转导，但它们的具体作用和贡献仍知之甚少。在这里，我们证明血管加压素 V 受体（VR）-βarr 复合物通过与 βarr 的直接相互作用在质膜上支架 Gβγ，使其能够转运到内体。Gβγ 随后增强 Gα 内体易位，可能是为了再生内体中异三聚体 G 的储备。这项工作揭示了 G 蛋白亚基从质膜到内体的易位的机制，并为理解 βarr 在介导持续的 G 蛋白信号转导中的作用提供了基础。
