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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., Competing Interests: CD, AG, HH, AW, IT, AT, BP No competing interests declared, (© 2023, Daly et al.)

Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility., Competing Interests: DZ, YS, MM, YW, HL, RL, ZL, YG, ZY, DH, AL, HM, YL, ML, WK, KC, FY, JL, YQ, JL, AT, AK, ZC, ZX, ML, DL, XY, JS No competing interests declared, (© 2018, Zhang et al.)