Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8475465 | Journal of Molecular and Cellular Cardiology | 2011 | 8 Pages |
Abstract
Two major β-adrenergic receptor (βAR) subtypes, β1AR and β2AR, are expressed in mammalian heart with β1AR coupling to Gs and β2AR dually coupling to Gs and Gi proteins. In many types of chronic heart failure, myocardial contractile response to both β1AR and β2AR stimulation is severely impaired. The dysfunction of βAR signaling in failing hearts is largely attributable to an increase in Gi signaling, because disruption of the Gi signaling restores myocardial contractile response to β1AR as well as β2AR stimulation. However, the mechanism terminating the β2AR-Gi signaling remains elusive, while it has been shown activation of the Gi signaling is dependent on agonist stimulation and subsequent PKA-mediated phosphorylation of the receptor. Here we demonstrate that regulator of G protein signaling 2 (RGS2) is a primary terminator of the β2AR-Gi signaling. Specifically, prolonged absence of agonist stimulation for 24 h impairs the β2AR-Gi signaling, resulting in enhanced β2AR- but not β1AR-mediated contractile response in cultured adult mouse cardiomyocytes. Increased β2AR contractile response is accompanied by a selective upregulation of RGS2 in the absence of alterations in other major cardiac RGS proteins (RGS3-5) or Gs, Gi or βAR subtypes. Administration of a βAR agonist, isoproterenol (ISO, 1.0 nM), prevents RGS2 upregulation and restores the β2AR-Gi signaling in cultured cells. Furthermore, RGS2 ablation, similar to βAR agonist stimulation, sustains the β2AR-Gi signaling in cultured cells, whereas adenoviral overexpression of RGS2 suppresses agonist-activated β2AR-Gi signaling in cardiomyocytes and HEK293 cells. These findings not only define RGS2 as a novel negative regulator of the β2AR-Gi signaling but also provide a potential novel target for the treatment of chronic heart failure.
Keywords
PTXGi proteinsCGP20712ATpeakt50m.o.i.PKIβARRGSRGS2AdVGPCRpKaERKCGPICI 118,551Adenovirusadenylyl cyclaseISOisoproterenolICIRegulator of G protein signalingpertussis toxinGAPwild typeGTPase-activating proteinprotein kinase Amultiplicity of infectionextracellular signal-regulated kinasesβ-Adrenergic receptorβ2-adrenergic receptorG protein-coupled receptor
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Authors
Khalid Chakir, Weizhong Zhu, Sharon Tsang, Anthony Yiu-Ho Woo, Dongmei Yang, Xianhua Wang, Xiaokun Zeng, Man-Hee Rhee, Ulrike Mende, Norimichi Koitabashi, Eiki Takimoto, Kendall J. Blumer, Edward G. Lakatta, David A. Kass, Rui-Ping Xiao,