title: RGS2 is a primary terminator of β₂-adrenergic receptor-mediated G(i) signaling.
abstract: Two major β-adrenergic receptor (βAR) subtypes, β(1)AR and β(2)AR, are expressed in mammalian heart with β(1)AR coupling to G(s) and β(2)AR dually coupling to G(s) and G(i) proteins. In many types of chronic heart failure, myocardial contractile response to both β(1)AR and β(2)AR 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 β(1)AR as well as β(2)AR stimulation. However, the mechanism terminating the β(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 β(2)AR-G(i) signaling. Specifically, prolonged absence of agonist stimulation for 24h impairs the β(2)AR-G(i) signaling, resulting in enhanced β(2)AR- but not β(1)AR-mediated contractile response in cultured adult mouse cardiomyocytes. Increased β(2)AR 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 β(2)AR-G(i) signaling in cultured cells. Furthermore, RGS2 ablation, similar to βAR agonist stimulation, sustains the β(2)AR-G(i) signaling in cultured cells, whereas adenoviral overexpression of RGS2 suppresses agonist-activated β(2)AR-G(i) signaling in cardiomyocytes and HEK293 cells. These findings not only define RGS2 as a novel negative regulator of the β(2)AR-G(i) signaling but also provide a potential novel target for the treatment of chronic heart failure.
authors.affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Chakir
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
authors.forename: Sharon
authors.initials: S
authors.lastname: Tsang
authors.forename: Anthony Yiu-Ho
authors.initials: AY
authors.lastname: Woo
authors.forename: Dongmei
authors.initials: D
authors.lastname: Yang
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Zeng
authors.forename: Man-Hee
authors.initials: MH
authors.lastname: Rhee
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
authors.forename: Norimichi
authors.initials: N
authors.lastname: Koitabashi
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Blumer
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D008024:Ligands; D020710:RGS Proteins; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs