The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development

Abstract

Heart failure (HF) is a global epidemic with the highest degree of mortality and morbidity of any disease presently studied. G protein-coupled receptors (GPCRs) are prominent regulators of cardiovascular function. Activated GPCRs are “turned off” by GPCR kinases (GRKs) in a process known as “desensitization”. GRKs 2 and 5 are highly expressed in the heart, and known to be upregulated in HF. Over the last 20 years, both GRK2 and GRK5 have been demonstrated to be critical mediators of the molecular alterations that occur in the failing heart. In the present review, we will highlight recent findings that further characterize "non-canonical" GRK signaling observed in HF. Further, we will also present potential therapeutic strategies (i.e. small molecule inhibition, microRNAs, gene therapy) that may have potential in combating the deleterious effects of GRKs in HF.

Noncanonical Roles of G Protein-coupled Receptor Kinases in Cardiovascular Signaling

“…Several mouse models support a critical and facilitative role for GRK2 in HF development. The role of GRK2 in the regulation of βAR signaling in the healthy and diseased myocardium and the pursuit for therapeutic inhibition of GRK2 has recently been reviewed in detail (42). …”

Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies

“…Overall, the aforementioned studies suggest consideration of GRK2 as a therapeutic target for cardiac disease and as a potential biomarker for heart function [64], [65] and [66]. …”

“…Oligonucleotide microarray left ventricular (LV) gene expression analysis performed in normal, failing and βARKct overexpressing (“rescued”) cardiac samples revealed the ability of βARKct to normalize gene expression changes associated with HF [74]. More recent studies performed in large animal HF models revealed preservation and amelioration of cardiac function along with normalization of CA signaling owing to stable myocardial βARKct gene delivery [75] and [76], suggesting that inhibition of Gβγ-GRK2 interactions with recombinant viral-delivered βARKct peptide is a promising therapy for HF treatment [66]. …”

“…In that perspective, small molecule inhibitors that could be administered systemically may represent an alternative approach to attenuate pathologic components of Gβγ-GRK2 signaling or interactions [64] and [66]. …”

“…Another potential strategy to interdict Gβγ-GRK2 pathologic signaling is targeting Gβγ subunit and inhibiting its protein-protein interactions [5] and [66]. Hence, Bonacci et al in 2006 performed a virtual screening of 1990 compounds from the National Cancer Institute (NCI) chemical library to identify small molecules capable of binding Gβγ protein interaction domain mentioned above [79].…”