GRK2 in cardiovascular disease and its potential as a therapeutic target

J Mol Cell Cardiol. 2022 Nov:172:14-23. doi: 10.1016/j.yjmcc.2022.07.008. Epub 2022 Jul 22.


Cardiovascular diseases (CVDs) represent the leading cause of death globally. Despite major advances in the field of pharmacological CVD treatments, particularly in the field of heart failure (HF) research, case numbers and overall mortality remain high and have trended upwards over the last few years. Thus, identifying novel molecular targets for developing HF therapeutics remains a key research focus. G protein-coupled receptors (GPCRs) are critical myocardial signal transducers which regulate cardiac contractility, growth, adaptation and metabolism. Additionally, GPCR dysregulation underlies multiple models of cardiac pathology, and most pharmacological therapeutics currently used in HF target these receptors. Currently-approved treatments have improved patient outcomes, but therapies to stop or reverse HF are lacking. A recent focus on GPCR intracellular-regulating proteins such as GPCR kinases (GRKs) has uncovered GRK2 as a promising target for combating HF. Current literature strongly establishes increased levels and activity of GRK2 in multiple models of CVD. Additionally, the GRK2 interactome includes numerous proteins which interact with differential domains of GRK2 to modulate both beneficial and deleterious signaling pathways in the heart, indicating that these domains can be targeted with a high level of specificity unique to various cardiac pathologies. These data support the premise that GRK2 should be at the forefront of a novel investigative drug search. This perspective reviews cardiac GPCRs, describes the structure and functions of GRK2 in cardiac function and maladaptive pathology, and summarizes the ongoing and future research for targeting this critical kinase across cellular, animal and human models of cardiac dysfunction and HF.

Keywords: Cardiovascular disease; GPCR; GRK2; Heart failure; Paroxetine.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cardiovascular Diseases* / metabolism
  • G-Protein-Coupled Receptor Kinase 2* / metabolism
  • Heart Failure*
  • Humans
  • Myocardium / metabolism
  • Receptors, G-Protein-Coupled / metabolism


  • G-Protein-Coupled Receptor Kinase 2
  • Receptors, G-Protein-Coupled
  • GRK2 protein, human