G protein-coupled receptor kinase 2 as a therapeutic target for heart failure

G protein-coupled receptor kinase 2 (GRK2), an important subtype of GRKs, specifically phosphorylates agonist-activated G protein-coupled receptors (GPCRs). Besides, current research confirms that it participates in multiple regulation of diverse cells via a non-phosphorylated pathway, including interacting with various non-receptor substrates and binding partners. Fibrosis is a common pathophysiological phenomenon in the repair process of many tissues due to various pathogenic factors such as inflammation, injury, drugs, etc. The characteristics of fibrosis are the activation of fibroblasts leading to myofibroblast proliferation and differentiation, subsequent aggerate excessive deposition of extracellular matrix (ECM). Then, a positive feedback loop is occurred between tissue stiffness caused by ECM and fibroblasts, ultimately resulting in distortion of organ architecture and function. At present, GRK2, which has been described as a multifunctional protein, regulates copious signaling pathways under pathophysiological conditions correlated with fibrotic diseases. Along with GRK2-mediated regulation, there are diverse effects on the growth and apoptosis of different cells, inflammatory response and deposition of ECM, which are essential in organ fibrosis progression. This review is to highlight the relationship between GRK2 and fibrotic diseases based on recent research. It is becoming more convincing that GRK2 could be considered as a potential therapeutic target in many fibrotic diseases.

Download Full-text

Cardiac hyporesponsiveness in severe sepsis is associated with nitric oxide-dependent activation of G protein receptor kinase

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00052.2016 ◽

2017 ◽

Vol 313 (1) ◽

pp. H149-H163 ◽

Cited By ~ 11

Author(s):

Daniela Dal-Secco ◽

Silvia DalBó ◽

Natalia E. S. Lautherbach ◽

Fábio N. Gava ◽

Mara R. N. Celes ◽

...

Keyword(s):

Nitric Oxide ◽

G Protein ◽

Cardiac Dysfunction ◽

Therapeutic Target ◽

Adrenergic Receptor ◽

Receptor Density ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

Potential Therapeutic Target ◽

G Protein Coupled

G protein-coupled receptor kinase isoform 2 (GRK2) has a critical role in physiological and pharmacological responses to endogenous and exogenous substances. Sepsis causes an important cardiovascular dysfunction in which nitric oxide (NO) has a relevant role. The present study aimed to assess the putative effect of inducible NO synthase (NOS2)-derived NO on the activity of GRK2 in the context of septic cardiac dysfunction. C57BL/6 mice were submitted to severe septic injury by cecal ligation and puncture (CLP). Heart function was assessed by isolated and perfused heart, echocardiography, and β-adrenergic receptor binding. GRK2 was determined by immunofluorescence and Western blot analysis in the heart and isolated cardiac myocytes. Sepsis increased NOS2 expression in the heart, increased plasma nitrite + nitrate levels, and reduced isoproterenol-induced isolated ventricle contraction, whole heart tension development, and β-adrenergic receptor density. Treatment with 1400W or with GRK2 inhibitor prevented CLP-induced cardiac hyporesponsiveness 12 and 24 h after CLP. Increased labeling of total and phosphorylated GRK2 was detected in hearts after CLP. With treatment of 1400W or in hearts taken from septic NOS2 knockout mice, the activation of GRK2 was reduced. 1400W or GRK2 inhibitor reduced mortality, improved echocardiographic cardiac parameters, and prevented organ damage. Therefore, during sepsis, NOS2-derived NO increases GRK2, which leads to a reduction in β-adrenergic receptor density, contributing to the heart dysfunction. Isolated cardiac myocyte data indicate that NO acts through the soluble guanylyl cyclase/cGMP/PKG pathway. GRK2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction. NEW & NOTEWORTHY The main novelty presented here is to show that septic shock induces cardiac hyporesponsiveness to isoproterenol by a mechanism dependent on nitric oxide and mediated by G protein-coupled receptor kinase isoform 2. Therefore, G protein-coupled receptor kinase isoform 2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction.

Download Full-text

Abstract 1060: Regulation of Protease Activated Receptor-1 signaling by G-protein coupled receptor kinase 3

Circulation ◽

10.1161/circ.116.suppl_16.ii_212-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Liam M Casey ◽

Jason Greenman ◽

Frederick Aguilar ◽

Olga Dunaevsky ◽

Burns C Blaxall

Keyword(s):

Heart Failure ◽

G Protein ◽

Ischemic Injury ◽

Neonatal Rat ◽

Cell Surface Receptor ◽

Immunofluorescent Staining ◽

Nuclear Accumulation ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) play crucial roles in normal heart function and dysregulated GPCR signaling contributes to heart failure (HF). Protease-activated receptors (PARs) are one class of GPCR expressed in the heart. Emerging evidence demonstrates that excessive PAR-1 signaling induces cardiac dysfunction. An important component of PAR signaling is ERK1/2, which is phosphorylated in response to PAR stimulation and can influence myocyte hypertrophy and survival. Cytoplasmic pERK1/2 accumulation depends in part on scaffolding complexes that assemble with internalized GPCRs. Activation of an internalization-defective PAR mutant leads to enhanced nuclear pERK1/2 accumulation upon stimulation. The nuclear/cytoplasmic distribution of pERK1/2 may be a key factor in determining the cellular effects of PAR stimulation as elevated nuclear pERK in cardiomyocytes is suggested to promote survival and physiological hypertrophy. Phosphorylation of PARs by G-protein coupled receptor kinase 3 (GRK3) is thought to promote receptor internalization, potentially influencing overall pERK1/2 accumulation and subcellular distribution. We have used a dominant negative form of GRK3 lacking the kinase domain (GRK3ct) to test the hypothesis that GRK3 influences PAR1 internalization and ERK1/2 phosphorylation. By measuring cell surface receptor levels we demonstrate that GRK3ct interferes with PAR1 internalization. Immunofluorescent staining and cellular fractionation techniques further show that GRK3ct enhances nuclear accumulation of pERK1/2 in COS-7 cells and adult mouse cardiomyocytes. Furthermore we find that GRK3ct overexpression in neonatal rat cardiomyocytes increases PAR1-activation induced physiologic hypertrophy. In summary these results may explain recent unpublished reports that mice overexpressing GRK3ct in the heart are protected against ischemic injury, a heart failure model that involves pathologic PAR signaling. Thus we conclude that following ischemic injury, reducing PAR1 internalization via interfering with endogenous GRK3 activity or promoting nuclear pERK accumulation might improve cardiac recovery.

Download Full-text