title: beta-Arrestin-dependent activation of Ca(2+)/calmodulin kinase II after beta(1)-adrenergic receptor stimulation.
abstract: Ca(2+)/calmodulin kinase II (CaMKII) plays an important role in cardiac contractility and the development of heart failure. Although stimulation of beta(1)-adrenergic receptors (ARs) leads to an increase in CaMKII activity, the molecular mechanism by which beta(1)-ARs activate CaMKII is not completely understood. In this study, we show the requirement for the beta(1)-AR regulatory protein beta-arrestin as a scaffold for both CaMKII and Epac (exchange protein directly activated by cAMP). Stimulation of beta(1)-ARs induces the formation of a beta-arrestin-CaMKII-Epac1 complex, allowing its recruitment to the plasma membrane, whereby interaction with cAMP leads to CaMKII activation. beta-Arrestin binding to the carboxyl-terminal tail of beta(1)-ARs promotes a conformational change within beta-arrestin that allows CaMKII and Epac to remain in a stable complex with the receptor. The essential role for beta-arrestin and identification of the molecular mechanism by which only beta(1)-ARs and not beta(2)-ARs activate CaMKII significantly advances our understanding of this important cellular pathway.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Supachoke
authors.initials: S
authors.lastname: Mangmool
authors.forename: Arun K
authors.initials: AK
authors.lastname: Shukla
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D018342:Receptors, Adrenergic, beta-1; D000071557:beta-Arrestins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2