GRK2 in the heart: a GPCR kinase and beyond.
CONCLUSIONS
Heart failure (HF) is a common end point for many underlying cardiovascular diseases. Down-regulation and desensitization of β-adrenergic receptors (β-AR) caused by G-protein-coupled receptor (GPCR) kinase 2 (GRK2) are prominent features of HF. Recent Advances and Critical Issues: Significant progress has been made to understand the pathological role of GRK2 in the heart both as a GPCR kinase and as a molecule that can exert GPCR-independent effects. Inhibition of cardiac GRK2 has proved to be therapeutic in the failing heart and may offer synergistic and additional benefits to β-blocker therapy. However, the mechanisms of how GRK2 directly contributes to the pathogenesis of HF need further investigation, and additional verification of the mechanistic details are needed before GRK2 inhibition can be used for the treatment of HF.


CONCLUSIONS
The newly identified characteristics of GRK2, including the S-nitrosylation of GRK2 and the localization of GRK2 on mitochondria, merit further investigation. They may contribute to it being a pro-death kinase and result in HF under stressed conditions through regulation of intracellular signaling, including cardiac reduction-oxidation (redox) balance. A thorough understanding of the functions of GRK2 in the heart is necessary in order to finalize it as a candidate for drug development.
Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine , Philadelphia, Pennsylvania.
Zheng Maggie
ZM
Huang
Erhe
E
Gao
J Kurt
JK
Chuprun
Walter J
WJ
Koch
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D015195:Drug Design; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D015316:Genetic Therapy; D006333:Heart Failure / Q000201:enzymology* / Q000378:metabolism / Q000628:therapy; D006801:Humans; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D011943:Receptors, Adrenergic, beta / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2