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G protein–coupled receptors (GPCRs) promote the expression of immediate early genes required for learning and memory. Here, we showed that β₂-adrenergic receptor (β₂AR) stimulation induced the nuclear export of phosphodiesterase 4D5 (PDE4D5), an enzyme that degrades the second messenger cAMP, to enable memory consolidation. We demonstrated that the endocytosis of β₂AR phosphorylated by GPCR kinases (GRKs) mediated arrestin3-dependent nuclear export of PDE4D5, which was critical for promoting nuclear cAMP signaling and gene expression in hippocampal neurons for memory consolidation. Inhibition of the arrestin3-PDE4D5 association prevented β₂AR-induced nuclear cAMP signaling without affecting receptor endocytosis. Direct PDE4 inhibition rescued β₂AR-induced nuclear cAMP signaling and ameliorated memory deficits in mice expressing a form of the β₂AR that could not be …