GRK2 and GRK5-The 2 critical kinases in cardiac pathophysiology.
G protein-coupled receptor kinases (GRKs) are a class of serine/threonine kinases that shut down active signaling mediated by agonist-bound G protein-coupled receptors. Of all the diseases that arise from dysfunctional G protein-coupled receptor-GRK interactions, this review will focus on the roles of the 2 most highly expressed GRKs in heart failure (HF)-GRK2 and GRK5. Both are upregulated in human and mouse HF heart samples. Because both GRK2 and GRK5 are expressed in all cardiac cell types-cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, and cardiomyocytes-it is essential to examine their role in these individual cell types for identifying specific cardiomyopathies and targeting them accordingly. Seminal work from our laboratory over the last 3 decades has uncovered multiple crucial aspects of GRK2- and GRK5-mediated interactions that lead to HF. Based on that, several GRK2 and GRK5 inhibitors have been identified/generated that have high potency and have been tested in multiple animal models of HF. One of the GRK2 inhibitors, paroxetine, has also been evaluated in 2 clinical trials. Similarly, potent GRK5 inhibitors have also been recently generated, and it remains to be seen how they affect cardiac structure and function in vivo. Lastly, assessing cell-specific fine differences in GRK2 and GRK5 inhibition will pave the way for identifying ideal patient cohorts for clinical trials in which selective GRK2 and GRK5 inhibitors can be evaluated as a new class of drugs for HF. SIGNIFICANCE STATEMENT: G protein-coupled receptor kinases 2 and 5 play a central role in heart failure (HF) onset and progression. They have critical significance in all cardiac cells, which contribute to the pathophysiology of HF, namely, cardiomyocytes, cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells. Dysfunction in their canonical G protein-coupled receptor-related function or noncanonical function must be sufficiently investigated and addressed to evaluate their inhibitors as a new class of drugs for HF.