βARKct: A Therapeutic Approach for Improved Adrenergic Signaling and Function in Heart Disease

One of the most powerful regulators of cardiovascular function is catecholamine-stimulated adrenergic receptor (AR) signaling. The failing heart is characterized by desensitization and impaired β-AR responsiveness as a result of upregulated G protein-coupled receptor kinase-2 (GRK2) present in injured myocardium. Deterioration of cardiac function is progressively enhanced by chronic adrenergic over-stimulation due to increased levels of circulating catecholamines. Increased GRK2 activity contributes to this pathological cycle of over-stimulation but lowered responsiveness. Over the past two decades the GRK2 inhibitory peptide βARKct has been identified as a potential therapy that is able to break this vicious cycle of self-perpetuating deregulation of the β-AR system and subsequent myocardial malfunction, thus halting development of cardiac failure. The βARKct has been shown to interfere with GRK2 binding to the βγ subunits of the heterotrimeric G protein, therefore inhibiting its recruitment to the plasma membrane that normally leads to phosphory-lation and internalization of the receptor. In this article we summarize the current data on the therapeutic effects of βARKct in cardiovascular disease and report on recent and ongoing studies that may pave the way for this peptide towards therapeutic application in heart failure and other states of cardiovascular disease.