Gi-Biased β2AR Signaling Links GRK2 Upregulation to Heart Failure
Rationale: Phosphorylation of β2-adrenergic receptor (β2AR) 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 β2AR to the receptor coupling to Gi 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 Gi-dependent decrease of contractile response to βAR stimulation in cultured mouse cardiomyocytes and in vivo. Importantly, cardiac-specific transgenic overexpression of a mutant β2AR lacking PKA phosphorylation sites (PKA-TG) but not the wild-type β2AR (WT-TG) or a mutant β2AR 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 Gi signaling with pertussis toxin restores cardiac function in heart failure associated with increased β2AR to Gi coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of β2AR by GRK and resultant increase in Gi-biased β2AR signaling play an important role in the development of heart failure.
Conclusions: Our data show that enhanced β2AR phosphorylation by GRK, in addition to PKA, leads the receptor to Gi-biased signaling, which, in turn, contributes to the pathogenesis of heart failure, marking Gi-biased β2AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression.
- Received July 22, 2011.
- Revision received November 9, 2011.
- Accepted December 5, 2011.
- © 2011 American Heart Association, Inc.