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Learning and memory‐related behaviors depend on GPCR signaling to the nucleus to induce Immediate early gene (IEG) expression. However, the molecular mechanisms mediating this process remain unclear. We have previously identified a subpopulation of β₂AR which is preferentially phosphorylated by GRK sites and internalized to the endosome upon stimulation. Here, we demonstrate that GRK phosphorylated endosomal β₂Adrenergic Receptor (β₂AR) indirectly facilitates nuclear cAMP signaling through sequestration of a PDE4D/β‐arrestin complex. Combining subcellular cAMP biosensors and transgenic mice, we found deleting GRK phosphorylation sites on β₂AR (GRKD) blocked agonist‐induced receptor endocytosis and nuclear cAMP signaling in hippocampal neurons. This resulted in impaired PKA‐mediated IEGs expression in vitro,reduced learning induced IEG expression in vivo, and impaired …