Myocardial G protein-coupled receptor kinases: implications for heart failure therapy.
The beta-adrenergic signaling cascade is an important regulator of myocardial function. Significant alterations of this pathway are associated with several cardiovascular diseases, including congestive heart failure (CHF). Included in these alterations is increased activity and expression of G protein-coupled receptor kinases (GRKs), such as the beta-adrenergic receptor kinase (beta ARK1), which phosphorylate and desensitize beta-adrenergic receptors (beta ARs). A body of evidence is accumulating that suggests that GRKs, in particular beta ARK1, are critical determinants of cardiac function under normal conditions and in disease states. Transgenic mice with myocardial-targeted alterations of GRK activity have shown profound changes in the in vivo functional performance of the heart. Included in these studies is the compelling finding that inhibition of beta ARK1 activity or expression significantly enhances cardiac function and potentiates beta AR signaling in failing cardiomyocytes. This article summarizes the advances made in the study of beta ARK1 in the heart and addresses its potential as a novel therapeutic target for CHF.
Iaccarino
G
G
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Lefkowitz
R J
RJ
Koch
W J
WJ
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D054770:G-Protein-Coupled Receptor Kinase 3; D054774:G-Protein-Coupled Receptor Kinase 5; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000378:metabolism; D051552:beta-Adrenergic Receptor Kinases
D004791:Enzyme Inhibitors; D011943:Receptors, Adrenergic, beta; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human; C517850:GRK3 protein, mouse; D051552:beta-Adrenergic Receptor Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human; C517895:Grk5 protein, mouse