Schematic diagram representing the essential role of β-arrestin for CaMKII signaling. Agonist binding to β₁-ARs leads to G protein coupling, cAMP generation, and activation of PKA signaling. GRK-mediated receptor phosphorylation results in β-arrestin recruitment, which induces a unique conformation in β-arrestin allowing stable interaction with CaMKII and Epac at the plasma membrane. β-Arrestin–mediated translocation of CaMKII and Epac to the β₁-AR complex brings these molecules in close proximity to the location of cAMP generation by AC. cAMP directly binds to and stimulates Epac, which leads to CaMKII activation via a Rap–PLC-ε–PKC-ε mechanism, and subsequent phosphorylation of downstream effectors.