G protein-coupled receptor kinases as therapeutic targets in the heart

• Published in: Nature reviews cardiology 2019-10, Vol.16 (10), p.612-622
• Main Authors: Pfleger, Jessica, Gresham, Kenneth, Koch, Walter J.
• Format: Article
• Language: English
• Subjects: 692/4019/592/75/230; 692/700/565; Adrenergic beta-Antagonists - therapeutic use; Analysis; Angiotensin II receptor blockers; Animals; beta-Arrestins - metabolism; Cardiac Imaging; Cardiac Surgery; Cardiology; Cardiomyocytes; Cardiovascular diseases; Care and treatment; Catecholamines - metabolism; Cyclic AMP-Dependent Protein Kinases - genetics; Diagnosis; Dosage and administration; G proteins; G-Protein-Coupled Receptor Kinase 2 - antagonists & inhibitors; G-Protein-Coupled Receptor Kinase 2 - metabolism; G-Protein-Coupled Receptor Kinase 5 - antagonists & inhibitors; G-Protein-Coupled Receptor Kinase 5 - metabolism; G-Protein-Coupled Receptor Kinases - antagonists & inhibitors; G-Protein-Coupled Receptor Kinases - metabolism; Heart Diseases - drug therapy; Heart Diseases - physiopathology; Heart failure; Heart Failure - drug therapy; Heart Failure - physiopathology; Humans; Kinases; Medicine; Medicine & Public Health; Muscle Contraction; Myocytes, Cardiac; Peptide Fragments - genetics; Physiology; Proteins; Receptors, Adrenergic - metabolism; Recombinant Proteins - genetics; Review Article; Risk factors; Signal Transduction - genetics
• ISSN: 1759-5002; 1759-5010
• DOI: 10.1038/s41569-019-0220-3

G protein-coupled receptors (GPCRs) are critical cellular sensors that mediate numerous physiological processes. In the heart, multiple GPCRs are expressed on various cell types, where they coordinate to regulate cardiac function by modulating critical processes such as contractility and blood flow. Under pathological settings, these receptors undergo aberrant changes in expression levels, localization and capacity to couple to downstream signalling pathways. Conventional therapies for heart failure work by targeting GPCRs, such as β-adrenergic receptor and angiotensin II receptor antagonists. Although these treatments have improved patient survival, heart failure remains one of the leading causes of mortality worldwide. GPCR kinases (GRKs) are responsible for GPCR phosphorylation and, therefore, desensitization and downregulation of GPCRs. In this Review, we discuss the GPCR signalling pathways and the GRKs involved in the pathophysiology of heart disease. Given that increased expression and activity of GRK2 and GRK5 contribute to the loss of contractile reserve in the stressed and failing heart, inhibition of overactive GRKs has been proposed as a novel therapeutic approach to treat heart failure. G protein-coupled receptor (GPCR) kinases (GRKs) can desensitize and downregulate GPCRs. In this Review, Pfleger and colleagues describe the changes in GPCR and GRK signalling in the heart under disease conditions and how GRKs can be targeted to treat heart failure. Key points G protein-coupled receptors (GPCRs) mediate a range of physiological responses in various cardiovascular cell types. β-Adrenergic receptors (β-ARs) regulate cardiomyocyte contractility in response to sympathetic nervous system stimulation. In the failing heart, increased levels of GPCR kinases (GRKs) phosphorylate, and thereby desensitize and downregulate, β-ARs, resulting in a loss of cardiomyocyte contractile reserve. GRK2 and GRK5 can be therapeutically targeted to protect the heart against injury and failure using novel small-molecule inhibitors.