GRK2 blockade with βARKct is essential for cardiac β(2)-adrenergic receptor signaling towards increased contractility

BACKGROUND: β(1)- and β(2)–adrenergic receptors (ARs) play distinct roles in the heart, e.g. β(1)AR is pro-contractile and pro-apoptotic but β(2)AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β(2)AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β(2)AR signaling under normal conditions and in heart failure (HF). RESULTS: We crossed β(1)AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β(2)AR-dependent contractile function, as β(2)AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β(2)AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular “brake” that PDE4D poses on β(2)AR signaling to contractility stimulation is thus “released”. Regarding the other beneficial functions of cardiac β(2)AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed. CONCLUSIONS: GRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β(2)AR pro-contractile signaling and function. In addition, β(2)AR anti-apoptotic signaling in post-MI HF is augmented by βARKct, although this effect is short-lived.