ß
1
- and ß
2
-adrenergic receptors (ßARs) are G-protein coupled receptors (GPCRs) that play clearly distinct roles in cardiac physiology/pathology: cardiomyocyte contraction is readily stimulated by ß
1
AR but not ß
2
AR signaling, and ß
1
AR signaling is largely pro-apoptotic in the heart, in contrast to the cardioprotective ß
2
AR signaling. These differences might be due to assembly of different macromolecular complexes containing phosphodiesterases (PDEs), which constrain pro-contractile 3'-5'-adenosine monophosphate (cAMP) signaling. Additionally, ß
2
AR is readily phosphorylated by GPCR kinase (GRK)-2, which then recruits ß-arrestin (ßarr), a universal GPCR adapter/scaffolding molecule, to the receptor. ßarrs reduce ß
2
AR pro-contractile signaling by desensitizing the receptor and can either increase or decrease apoptosis via interactions with several downstream effectors. Herein, we sought to investigate the effect of ßarr recruitment blockade on ß
2
AR-dependent contractility and survival in vivo. To this end, we crossed ß
1
AR knockout (B1KO) mice, lacking the ß
1
AR, with M27 mice, which overexpress, specifically in cardiac myocytes, the GRK2 inhibitor GRK2ct (or ßARKct). By blocking GRK2-mediated phosphorylation, ßarr binding to ß
2
AR is prevented. We studied the offspring both under normal conditions and after surgically induced myocardial infarction (MI). Contractility was significantly augmented in M27/B1KO mice compared to control B1KO's, both in healthy mice (ejection fraction (EF): 69+1.8% vs. 57+1.7%, respectively, p<0.05, n=8) and at 4 weeks post-MI (EF: 42.6+0.1% vs. 25+3.9%, respectively, p<0.05, n=8). In addition, M27/B1KO mice exhibited less cardiac dilatation, increased survival and decreased cardiac apoptosis and infarct size, compared to B1KO's, at 4 weeks post-MI. At the molecular level, M27/B1KO hearts displayed significantly less membrane recruitment of PDEs, upregulation of the anti-apoptotic Bcl-2 and a more favorable inflammatory cytokine profile vs. B1KO hearts. Thus, cardiac GRK2 inhibition by GRK2ct increases both ß
2
AR-dependent contractility and survival in post-MI heart failure and could be pursued in situations where ß
2
AR agonism is beneficial, e.g. in patients awaiting cardiac transplantation.
β2-adrenergic receptor regulates ER-mitochondria contacts
