β-Arrestin–dependent activation of Ca(2+)/calmodulin kinase II after β(1)–adrenergic receptor stimulation

Ca(2+)/calmodulin kinase II (CaMKII) plays an important role in cardiac contractility and the development of heart failure. Although stimulation of β(1)–adrenergic receptors (ARs) leads to an increase in CaMKII activity, the molecular mechanism by which β(1)-ARs activate CaMKII is not completely understood. In this study, we show the requirement for the β(1)-AR regulatory protein β-arrestin as a scaffold for both CaMKII and Epac (exchange protein directly activated by cAMP). Stimulation of β(1)-ARs induces the formation of a β-arrestin–CaMKII–Epac1 complex, allowing its recruitment to the plasma membrane, whereby interaction with cAMP leads to CaMKII activation. β-Arrestin binding to the carboxyl-terminal tail of β(1)-ARs promotes a conformational change within β-arrestin that allows CaMKII and Epac to remain in a stable complex with the receptor. The essential role for β-arrestin and identification of the molecular mechanism by which only β(1)-ARs and not β(2)-ARs activate CaMKII significantly advances our understanding of this important cellular pathway.