Role of the V2R–βarrestin–Gβγ complex in promoting G protein translocation to endosomes

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 V ₂ receptor (V ₂R)–βarr complex scaffolds Gβγ at the plasma membrane through a direct interaction with βarr, enabling its transport to endosomes. Gβγ subsequently potentiates Gα _s endosomal translocation, presumably to regenerate an endosomal pool of heterotrimeric G _s. 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.

Abstract

A V2R–βarrestin–Gβγ complex forms at the plasma membrane and translocates to endosomes. This sheds light on G protein subunit translocation and βarr’s role in sustained signaling.