| First Author | Zhu W | Year | 2012 |
| Journal | Circ Res | Volume | 110 |
| Issue | 2 | Pages | 265-74 |
| PubMed ID | 22179058 | Mgi Jnum | J:192705 |
| Mgi Id | MGI:5466229 | Doi | 10.1161/CIRCRESAHA.111.253260 |
| Citation | Zhu W, et al. (2012) Gi-biased beta2AR signaling links GRK2 upregulation to heart failure. Circ Res 110(2):265-74 |
| abstractText | RATIONALE: Phosphorylation of beta(2)-adrenergic receptor (beta(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 beta(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. METHODS AND RESULTS: Overexpression of GRK2 led to a G(i)-dependent decrease of contractile response to betaAR stimulation in cultured mouse cardiomyocytes and in vivo. Importantly, cardiac-specific transgenic overexpression of a mutant beta(2)AR lacking PKA phosphorylation sites (PKA-TG) but not the wild-type beta(2)AR (WT-TG) or a mutant beta(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 beta(2)AR to G(i) coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of beta(2)AR by GRK and resultant increase in G(i)-biased beta(2)AR signaling play an important role in the development of heart failure. CONCLUSIONS: Our data show that enhanced beta(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 beta(2)AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression. |
