β-Arrestin–dependent activation of Ca2+/calmodulin kinase II after β1–adrenergic receptor stimulation

Abstract

Ca2+/calmodulin kinase II (CaMKII) plays an important role in cardiac contractility and the development of heart failure. Although stimulation of β1–adrenergic receptors (ARs) leads to an increase in CaMKII activity, the molecular mechanism by which β1-ARs activate CaMKII is not completely understood. In this study, we show the requirement for the β1-AR regulatory protein β-arrestin as a scaffold for both CaMKII and Epac (exchange protein directly activated by cAMP). Stimulation of β1-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 β1-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 β1-ARs and not β2-ARs activate CaMKII significantly advances our understanding of this important cellular pathway.