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

Two major β-adrenergic receptor (βAR) subtypes, β₁AR and β₂AR, are expressed in mammalian heart with β₁AR coupling to G_s and β₂AR dually coupling to G_s and G_i 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 G_i signaling, because disruption of the G_i signaling restores myocardial contractile response to β₁AR as well as β₂AR stimulation. However, the mechanism terminating the β₂AR-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 β₂AR-G_i signaling. Specifically, prolonged absence of agonist stimulation for 24h impairs the β₂AR-G_i 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 G_s, G_i or βAR subtypes. Administration of a βAR agonist, isoproterenol (ISO, 1.0 nM), prevents RGS2 upregulation and restores the β₂AR-G_i signaling in cultured cells. Furthermore, RGS2 ablation, similar to βAR agonist stimulation, sustains the β₂AR-G_i signaling in cultured cells, whereas adenoviral overexpression of RGS2 suppresses agonist-activated β₂AR-G_i signaling in cardiomyocytes and HEK293 cells. These findings not only define RGS2 as a novel negative regulator of the β₂AR-G_i signaling but also provide a potential novel target for the treatment of chronic heart failure.