Background:Cross-talk between GPCRs is an important but undercharacterized mechanism regulating receptor responsiveness. Results:Co-activation of β and α ARs accelerates α AR endocytosis in a PKA- and spinophilin-dependent fashion. Conclusion:βAR-mediated signaling modulates α AR endocytosis via PKA-dependent disruption of α AR/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. 2 2A 2A 2A