RGS2 is a primary terminator of β2-adrenergic receptor-mediated Gi signaling

Two major beta-adrenergic receptor (beta AR) subtypes, beta(1)AR and beta(2)AR, are expressed in mammalian heart with beta(1)AR coupling to G(s) and beta(2)AR dually coupling to G(s) and G(i) proteins. In many types of chronic heart failure, myocardial contractile response to both beta(1)AR and beta(2)AR stimulation is severely impaired. The dysfunction of beta AR signaling in failing hearts is largely attributable to an increase in G(i) signaling, because disruption of the G(i) signaling restores myocardial contractile response to beta(1)AR as well as beta(2)AR stimulation. However, the mechanism terminating the beta(2)AR-G(i) signaling remains elusive, while it has been shown activation of the G(i) 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 beta(2)AR-G(i) signaling. Specifically, prolonged absence of agonist stimulation for 24 h impairs the beta(2)AR-G(i) signaling, resulting in enhanced beta(2)AR-but not beta(1)AR-mediated contractile response in cultured adult mouse cardiomyocytes. Increased beta(2)AR contractile response is accompanied by a selective upregulation of RGS2 in the absence of alterations in other major cardiac RCS proteins (RGS3-5) or G(s), G(i) or beta AR subtypes. Administration of a beta AR agonist, isoproterenol (ISO, 1.0 nM), prevents RGS2 upregulation and restores the beta AR-G(i) signaling in cultured cells. Furthermore, RGS2 ablation, similar to beta AR agonist stimulation, sustains the beta(2)AR-G(i) signaling in cultured cells, whereas adenoviral overexpression of RGS2 suppresses agonist-activated beta(2)AR-G(i) signaling in cardiomyocytes and HEK293 cells. These findings not only define RGS2 as a novel negative regulator of the beta(2)AR-G(i) signaling but also provide a potential novel target for the treatment of chronic heart failure. Published by Elsevier Ltd.