scholarly journals G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

2022 ◽  
Vol 12 ◽  
Author(s):  
Nan Li ◽  
Shan Shan ◽  
Xiu-Qin Li ◽  
Ting-Ting Chen ◽  
Meng Qi ◽  
...  
Keyword(s):  
G Protein ◽  
Therapeutic Target ◽  
Repair Process ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Multifunctional Protein ◽  
Pathogenic Factors ◽  
Fibrotic Diseases ◽  
And Function ◽  
G Protein Coupled

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.

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

2012 ◽  
Vol 9 (4) ◽  
pp. e155-e162 ◽  
Author(s):  
Sarah M. Schumacher-Bass ◽  
Christopher J. Traynham ◽  
Walter J. Koch
Keyword(s):  
Heart Failure ◽  
G Protein ◽  
Therapeutic Target ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

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

2017 ◽  
Vol 313 (1) ◽  
pp. H149-H163 ◽  
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.

scholarly journals Historical Perspective of the G Protein-Coupled Receptor Kinase Family

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 555
Author(s):  
Jeffrey L. Benovic
Keyword(s):  
G Protein ◽  
Historical Perspective ◽  
Heterotrimeric G Proteins ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
The Family ◽  
Primary Focus ◽  
And Function ◽  
G Protein Coupled

Agonist activation of G protein-coupled receptors promotes sequential interaction of the receptor with heterotrimeric G proteins, G protein-coupled receptor kinases (GRKs), and arrestins. GRKs play a central role in mediating the switch from G protein to arrestin interaction and thereby control processes such as receptor desensitization and trafficking and arrestin-mediated signaling. In this review, I provide a historical perspective on some of the early studies that identified the family of GRKs with a primary focus on the non-visual GRKs. These studies included identification, purification, and cloning of the β-adrenergic receptor kinase in the mid- to late-1980s and subsequent cloning and characterization of additional members of the GRK family. This helped to lay the groundwork for ensuing work focused on understanding the structure and function of these important enzymes.

scholarly journals Structure and Function of the Hypertension Variant A486V of G Protein-coupled Receptor Kinase 4

2015 ◽  
Vol 290 (33) ◽  
pp. 20360-20373 ◽  
Author(s):  
Samantha J. Allen ◽  
Gopal Parthasarathy ◽  
Paul L. Darke ◽  
Ronald E. Diehl ◽  
Rachael E. Ford ◽  
...  
Keyword(s):  
G Protein ◽  
Structure And Function ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
And Function ◽  
G Protein Coupled

scholarly journals G Protein-coupled Receptor Kinase 4 (GRK4) Regulates the Phosphorylation and Function of the Dopamine D3Receptor

2009 ◽  
Vol 284 (32) ◽  
pp. 21425-21434 ◽  
Author(s):  
Van Anthony M. Villar ◽  
John E. Jones ◽  
Ines Armando ◽  
Cynthia Palmes-Saloma ◽  
Peiying Yu ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
And Function ◽  
G Protein Coupled
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