“Freeze, Don’t Move”: How to Arrest a Suspect in Heart Failure – A Review on Available GRK2 Inhibitors

Abstract

Cardiovascular disease and heart failure (HF) still collect the largest toll of death in western societies and all over the world. A growing number of molecular mechanisms represent possible targets for new therapeutic strategies, which can counteract the metabolic and structural changes observed in the failing heart. G protein-coupled receptor kinase 2 (GRK2) is one of such targets for which experimental and clinical evidence are established. Indeed, several strategies have been carried out in place to interface with the known GRK2 mechanisms of action in the failing heart. This review deals with results from basic and preclinical studies. It shows different strategies to inhibit GRK2 in HF in vivo (βARK-ct gene therapy, treatment with gallein, and treatment with paroxetine) and in vitro (RNA aptamer, RKIP, and peptide-based inhibitors). These strategies are based either on the inhibition of the catalytic activity of the kinase (“Freeze!”) or the prevention of its shuttling within the cell (“Don’t Move!”). Here, we review the peculiarity of each strategy with regard to the ability to interact with the multiple tasks of GRK2 and the perspective development of eventual clinical use.

GRKs and β-Arrestins: “Gatekeepers” of Mitochondrial Function in the Failing Heart

“…G Protein-CoupledReceptor (GPCR) Kinase (GRKs) and β-arrestins are key regulators of GPCR signaling (Ferguson, 2001; Kohout and Lefkowitz, 2003; Santulli and Iaccarino, 2016; Sorriento et al, 2016). Indeed, GRKs are recruited to the plasma membrane when the receptor is activated by agonist binding.…”

GRK2 moderates the acute mitochondrial damage to ionizing radiation exposure by promoting mitochondrial fission/fusion

“…G-protein coupled receptor kinase 2 (GRK2) regulates multiple cellular functions 1 , 2 and is tightly regulated in a time and space-dependent manner by different stimuli or pathophysiological conditions 3 , 4 . Lately, the evidence that GRK2 can also localize in mitochondria through binding of HSP-90 in response to hypoxia or other stressful events 5 , 6 , supports the vision of GRK2 as a stress protein, opening a scenario of unexplored paradigms of signaling for the kinase, and prompting further investigation of specific molecular partners in mitochondrial regulation.…”

Phosphoproteomic-based kinase profiling early in influenza virus infection identifies GRK2 as antiviral drug target

“…Furthermore, beta-arrestin binding also triggers receptor internalization and subsequent lysosomal degradation 51 . Increased levels of GRK2 are therefore associated with a reduction in GPCR signaling and this is particularly well documented for beta-adrenergic receptor signaling in heart tissue, where increased levels of GRK2 are linked with impaired cardiac contractility 51 , 52 . Hence, GRK2 has emerged as promising drug target in heart disease and inhibitor development is under way 53 , 54 , which could eventually enable drug repurposing for the treatment of influenza virus infections.…”