GRK2 blockade with βARKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility

Background: beta(1)- and beta(2)-adrenergic receptors (ARs) play distinct roles in the heart, e. g. beta(1)AR is pro-contractile and pro-apoptotic but beta(2)AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes beta AR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (beta arr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the beta(2)AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on beta(2)AR signaling under normal conditions and in heart failure (HF). Results: We crossed beta(1)AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the beta ARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). beta ARKct expression in vivo proved essential for beta(2)AR-dependent contractile function, as beta(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 beta ARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac beta(2)AR, which is normally mediated by the actions of GRK2 and beta arrs on the receptor. The molecular brake that PDE4D poses on beta(2)AR signaling to contractility stimulation is thus released. Regarding the other beneficial functions of cardiac beta(2)AR, beta ARKct 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 beta ARKct is absolutely essential for cardiac beta(2)AR pro-contractile signaling and function. In addition, beta(2)AR anti-apoptotic signaling in post-MI HF is augmented by beta ARKct, although this effect is short-lived.