Arrestin-dependent nuclear export of phosphodiesterase 4D promotes GPCR-induced nuclear cAMP signaling required for...

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 phosphorylated by GRKs. These data reveal how β₂AR phosphorylated by endosomal GRK promotes the nuclear export of PDE4D5, leading to nuclear cAMP signaling, changes in gene expression, and memory consolidation. This study also highlights the translocation of PDEs as a mechanism to promote cAMP signaling in specific subcellular locations downstream of GPCR activation.