Background:Cross-talk between GPCRs is an important but undercharacterized mechanism regulating receptor responsiveness. Results:Co-activation of β and α2ARs accelerates α2AAR endocytosis in a PKA- and spinophilin-dependent fashion. Conclusion:βAR-mediated signaling modulates α2AAR endocytosis via PKA-dependent disruption of α2AAR/spinophilin interaction. Significance:Cross-talk from βto α2 ARs may have important implications in basal adrenergic tone and the pharmacology of commonly used adrenergic therapeutics. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.