beta-Arrestin-dependent activation of Ca(2+)/calmodulin kinase II after beta(1)-adrenergic receptor stimulation.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Mangmool, S; Shukla, AK; Rockman, HA
Published Date
- May 3, 2010
Published In
Volume / Issue
- 189 / 3
Start / End Page
- 573 - 587
PubMed ID
- 20421423
Pubmed Central ID
- PMC2867304
Electronic International Standard Serial Number (EISSN)
- 1540-8140
Digital Object Identifier (DOI)
- 10.1083/jcb.200911047
Language
- eng
Conference Location
- United States