title: Gi-biased β2AR signaling links GRK2 upregulation to heart failure.
abstract: BACKGROUND
  Phosphorylation of β(2)-adrenergic receptor (β(2)AR) by a family of serine/threonine kinases known as G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) is a critical determinant of cardiac function. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is a well-established causal factor of heart failure, but the underlying mechanism is poorly understood.
  
  
  OBJECTIVE
  We sought to determine the relative contribution of PKA- and GRK-mediated phosphorylation of β(2)AR to the receptor coupling to G(i) signaling that attenuates cardiac reserve and contributes to the pathogenesis of heart failure in response to pressure overload.
  
  
  RESULTS
  Overexpression of GRK2 led to a G(i)-dependent decrease of contractile response to βAR stimulation in cultured mouse cardiomyocytes and in vivo. Importantly, cardiac-specific transgenic overexpression of a mutant β(2)AR lacking PKA phosphorylation sites (PKA-TG) but not the wild-type β(2)AR (WT-TG) or a mutant β(2)AR lacking GRK sites (GRK-TG) led to exaggerated cardiac response to pressure overload, as manifested by markedly exacerbated cardiac maladaptive remodeling and failure and early mortality. Furthermore, inhibition of G(i) signaling with pertussis toxin restores cardiac function in heart failure associated with increased β(2)AR to G(i) coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of β(2)AR by GRK and resultant increase in G(i)-biased β(2)AR signaling play an important role in the development of heart failure.
  
  
  CONCLUSIONS
  Our data show that enhanced β(2)AR phosphorylation by GRK, in addition to PKA, leads the receptor to G(i)-biased signaling, which, in turn, contributes to the pathogenesis of heart failure, marking G(i)-biased β(2)AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China. Xiaor@pku.edu.cn; Weizhong Zhu, MD, PhD, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19107, USA. Weizhong.Zhu@Temple.edu
authors.forename: Weizhong
authors.initials: W
authors.lastname: Zhu
authors.forename: Natalia
authors.initials: N
authors.lastname: Petrashevskaya
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.forename: Aizhi
authors.initials: A
authors.lastname: Zhao
authors.forename: Khalid
authors.initials: K
authors.lastname: Chakir
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Talan
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
chemical_list: C553443:ADRB2 protein, human; D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go