Learning and memory-related behaviors in mammals depend on prototypical GPCR signaling and subsequent changes in gene expression. Immediate early gene (IEG) expression is necessary for memory and is induced by increased nuclear cyclic adenosine monophosphate (cAMP) signaling. However, the downstream mechanisms mediating this process have remained unclear. Here, we demonstrate in detail a surprising mechanism by which the G-protein coupled receptor (GPCR) β2 Adrenergic Receptor (β2AR) under stimulation indirectly facilitates nuclear cAMP signaling via sequestration of a phosphodiesterase (PDE)4D5/β-arrestin complex. By combining compartment localized cAMP biosensors, Förster resonance energy transfer (FRET)-based live cell imaging, immunofluorescent imaging, and transgenic mice, we found the following:• Deletion of G-protein receptor kinase (GRK) phosphorylation sites on β2AR (GRKΔ) blocked agonist-induced receptor internalization to the endosomal compartment. • This loss of GRK/arrestin mediated internalization also reduced nuclear cAMP in hippocampal neurons. • Loss of nuclear cAMP signaling impaired nuclear PKA-mediated immediate early genes (IEGs) expression in neurons. • In animals, loss of GRK phosphorylation resulted impairment of long-term memory in a Morris water maze, a deficit in learning induced IEG expression, but intact working memory. • In wildtype neurons, β2AR stimulation promoted internalization of the receptor to the endosome, and β-arrestin-dependent recruitment of cAMP-degrading PDE4D5 to the internalized receptor. • Intriguingly, inhibition of β-arrestin-PDE4D recruitment alone prevented β2AR-dependent increases in nuclear cAMP signaling in neurons and PDE4D5 recruitment. • Furthermore, direct PDE4 inhibition was sufficient to rescue the β2AR-dependent nuclear cAMP signal in vitro, and in vivo ameliorated the long-term memory deficits of GRKΔ mice. • PDE4D5 but not other PDE isoforms were found enriched in the nucleus of neurons and stimulation of β2AR causes the movement of PDE4D5 out of the nucleus into the cytosol. • Additionally, Stimulation with other GPCR agonists also caused ligand dependent trafficking of PDE4D5, suggesting the proposed mechanism may have implications for other Gs-coupled • Receptors. Additionally, we found removal of GRK phosphorylation sites on β2AR at serines 355/356 or knockout of β2AR resulted in aberrant anxiety response in the elevated plus Maze (EPM). • Furthermore, we show that knockout of β1AR results in a loss of both anxiety response in the EPM and acute stress response in a force swim test (FST). This work therefore indicates learning and memory relies critically upon the endosomal, GRK-phosphorylated β2AR sequestration of a β-arrestin/PDE4D complex, which indirectly facilitates nuclear cAMP signaling by effectively removing a PDE4D blockade of cAMP signaling from the nucleus. Therefore, these data constitute a novel and major mechanism by which learning and memory-related behaviors in mammals are regulated by GPCR signaling, at the endosome as well as suggest regulation of stress or memory controlled by different β-adrenergic subtype. These data also suggest differential βAR subtype regulation of stress response.