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.
- G protein-coupled receptor kinase
- heart failure
- β2-adrenergic receptor
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine