Gi-biased β2AR signaling links GRK2 upregulation to heart failure

Weizhong Zhu, Natalia Petrashevskaya, Shuxun Ren, Aizhi Zhao, Khalid Chakir, Erhe Gao, J. Kurt Chuprun, Yibin Wang, Mark Talan, Gerald W. Dorn, Edward G. Lakatta, Walter J. Koch, Arthur M. Feldman, Rui Ping Xiao

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Rationale: Phosphorylation of β 2-adrenergic receptor (β 2AR) 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 2AR 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. Methods and 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 2AR lacking PKA phosphorylation sites (PKA-TG) but not the wild-type β 2AR (WT-TG) or a mutant β 2AR 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 2AR to G i coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of β 2AR by GRK and resultant increase in G i-biased β 2AR signaling play an important role in the development of heart failure. Conclusions: Our data show that enhanced β 2AR 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 2AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression.

Original languageEnglish
Pages (from-to)265-274
Number of pages10
JournalCirculation research
Volume110
Issue number2
DOIs
StatePublished - Jan 20 2012

Keywords

  • G protein-coupled receptor kinase
  • heart failure
  • hypertrophy
  • β2-adrenergic receptor

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