Fig. 10.

ACKR3 GRK specificity is dependent on whether CXCR4 is co-activated. When expressed alone, the atypical receptor is primarily phosphorylated by GRK5, which drives agonist-mediated internalization and scavenging. In the context of CXCR4 co-expression, the co-activation of CXCR4 activates heterotrimeric G proteins and releases Gβγ, which recruits GRK2 and mediates phosphorylation of both receptors. This allows for ACKR3 to sense the activation of CXCR4 and then enhance the scavenging decoy responses of ACKR3. This image does not include the passive constitutive internalization and scavenging pathway. Image created with BioRender.