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.