Abstract 311: In vitro Regulation of G-protein Coupled Receptor Kinase 5 (GRK5) Induced Cardiac Hypertrophy by a Novel Interaction With the Phosphatase PHLPP2

2018 ◽  
Vol 123 (Suppl_1) ◽  
Author(s):  
Szu-Tsen Yeh ◽  
Cristina Zambrano ◽  
Walter Koch ◽  
Nicole Purcell
Keyword(s):  
Cardiac Hypertrophy ◽  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals α-Actinin is a potent regulator of G protein-coupled receptor kinase activity and substrate specificity in vitro

FEBS Letters ◽  
2000 ◽  
Vol 473 (3) ◽  
pp. 280-284 ◽  
Author(s):  
Jennifer L.R. Freeman ◽  
Julie A. Pitcher ◽  
Xiaolin Li ◽  
Vann Bennett ◽  
Robert J. Lefkowitz
Keyword(s):  
Substrate Specificity ◽  
G Protein ◽  
Kinase Activity ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals G Protein-coupled Receptor Kinase 2–mediated Phosphorylation of Ezrin Is Required for G Protein-coupled Receptor–dependent Reorganization of the Actin Cytoskeleton

2005 ◽  
Vol 16 (7) ◽  
pp. 3088-3099 ◽  
Author(s):  
Sarah H. Cant ◽  
Julie A. Pitcher
Keyword(s):  
G Protein ◽  
Phosphorylation Site ◽  
Rho Kinase ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Glutathione S Transferase ◽  
Membrane Ruffling ◽  
Gpcr Activation ◽  
G Protein Coupled

G protein-coupled receptor kinase 2 (GRK2) phosphorylates and desensitizes activated G protein-coupled receptors (GPCRs). Here, we identify ezrin as a novel non-GPCR substrate of GRK2. GRK2 phosphorylates glutathione S-transferase (GST)-ezrin, but not an ezrin fusion protein lacking threonine 567 (T567), in vitro. These results suggest that T567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of GRK2-mediated phosphorylation. Two lines of evidence indicate that GRK2-mediated ezrin-radixinmoesin (ERM) phosphorylation serves to link GPCR activation to cytoskeletal reorganization. First, in Hep2 cells muscarinic M1 receptor (M1MR) activation causes membrane ruffling. This ruffling response is ERM dependent and is accompanied by ERM phosphorylation. Inhibition of GRK2, but not rho kinase or protein kinase C, prevents ERM phosphorylation and membrane ruffling. Second, agonist-induced internalization of the β2-adrenergic receptor (β2AR) and M1MR is accompanied by ERM phosphorylation and localization of phosphorylated ERM to receptor-containing endocytic vesicles. The colocalization of internalized β2AR and phosphorylated ERM is not dependent on Na+/H+ exchanger regulatory factor binding to the β2AR. Inhibition of ezrin function impedes β2AR internalization, further linking GPCR activation, GRK activity, and ezrin function. Overall, our results suggest that GRK2 serves not only to attenuate but also to transduce GPCR-mediated signals.

scholarly journals An RNA molecule that specifically inhibits G-protein-coupled receptor kinase 2 in vitro

RNA ◽  
2008 ◽  
Vol 14 (3) ◽  
pp. 524-534 ◽  
Author(s):  
G. Mayer ◽  
B. Wulffen ◽  
C. Huber ◽  
J. Brockmann ◽  
B. Flicke ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

Human substance P receptor undergoes agonist-dependent phosphorylation by G protein-coupled receptor kinase 5 in vitro

FEBS Letters ◽  
2002 ◽  
Vol 521 (1-3) ◽  
pp. 140-144 ◽  
Author(s):  
Kengo Warabi ◽  
Mark D. Richardson ◽  
William T. Barry ◽  
Keisuke Yamaguchi ◽  
Eric D. Roush ◽  
...  
Keyword(s):  
Substance P ◽  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Substance P Receptor ◽  
G Protein Coupled

scholarly journals Hypothesis

2016 ◽  
Vol 22 (1) ◽  
pp. 51-53 ◽  
Author(s):  
Jonathan M. Powell ◽  
Emanuel Ebin ◽  
Steven Borzak ◽  
Anastasios Lymperopoulos ◽  
Charles H. Hennekens
Keyword(s):  
G Protein ◽  
Wall Thickness ◽  
Basic Research ◽  
Left Ventricular ◽  
Conditional Knockout ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

The hypothesis that paroxetine decreases morbidity and mortality in patients with heart failure (HF) is plausible but unproven. Basic research demonstrates that inhibition of G protein-coupled receptor kinase 2 (GRK2) both in vitro and in vivo in the myocardium may be beneficial. G protein-coupled receptor kinase 2 antagonism is purported to exert cardioprotective effects immediately following myocardial injury by blunting toxic overstimulation on a recently injured heart. In addition, chronic overexpression of GRK2 inhibits catecholamine induction of vital positive chronotropic and ionotropic effects required to preserve cardiac output leading to worsening of congestive HF. In cardiac-specific GRK2 conditional knockout mice, there is significant improvement in left ventricular wall thickness, left ventricular end-diastolic diameter (LVEDD), and ejection fraction (EF) compared to controls. Paroxetine is a selective serotonin reuptake inhibitor which was recently shown to have the ability to directly inhibit GRK2 both in vitro and in vivo. At physiologic temperatures, paroxetine inhibits GRK2-dependent phosphorylation of an activated G-protein-coupled receptor with a half maximal inhibitory concentration of 35 micromoles, a substantially greater affinity than for other G protein-coupled receptor kinases. In a randomized trial in mice with systolic HF and depressed EF postmyocardial infarction, those treated with paroxetine had a 30% increase in EF, improved contractility, and LVEDD and wall thickness compared to those treated with medical therapy alone. While further basic research may continue to elucidate plausible mechanisms of benefit and observational studies will contribute important relevant information, large scale randomized trials designed a priori to do so are necessary to test the hypothesis.

scholarly journals G-protein-coupled receptor kinase-2 is a critical regulator of TNFα signaling in colon epithelial cells

2017 ◽  
Vol 474 (14) ◽  
pp. 2301-2313 ◽  
Author(s):  
Michael D. Steury ◽  
Peter C. Lucas ◽  
Laura R. McCabe ◽  
Narayanan Parameswaran
Keyword(s):  
Wound Healing ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
G Protein ◽  
Critical Role ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

G-protein-coupled receptor kinase-2 (GRK2) belongs to the GRK family of serine/threonine protein kinases critical in the regulation of G-protein-coupled receptors. Apart from this canonical role, GRK2 is also involved in several signaling pathways via distinct intracellular interactomes. In the present study, we examined the role of GRK2 in TNFα signaling in colon epithelial cell–biological processes including wound healing, proliferation, apoptosis, and gene expression. Knockdown of GRK2 in the SW480 human colonic cells significantly enhanced TNFα-induced epithelial cell wound healing without any effect on apoptosis/proliferation. Consistent with wound-healing effects, GRK2 knockdown augmented TNFα-induced matrix metalloproteinases (MMPs) 7 and 9, as well as urokinase plasminogen activator (uPA; factors involved in cell migration and wound healing). To assess the mechanism by which GRK2 affects these physiological processes, we examined the role of GRK2 in TNFα-induced MAPK and NF-κB pathways. Our results demonstrate that while GRK2 knockdown inhibited TNFα-induced IκBα phosphorylation, activation of ERK was significantly enhanced in GRK2 knockdown cells. Our results further demonstrate that GRK2 inhibits TNFα-induced ERK activation by inhibiting generation of reactive oxygen species (ROS). Together, these data suggest that GRK2 plays a critical role in TNFα-induced wound healing by modulating MMP7 and 9 and uPA levels via the ROS–ERK pathway. Consistent with in vitro findings, GRK2 heterozygous mice exhibited enhanced intestinal wound healing. Together, our results identify a novel role for GRK2 in TNFα signaling in intestinal epithelial cells.

scholarly journals G protein-coupled receptor kinase 2 promotes cardiac hypertrophy

PLoS ONE ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. e0182110 ◽  
Author(s):  
Philipp Schlegel ◽  
Julia Reinkober ◽  
Eric Meinhardt ◽  
Henrike Tscheschner ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
G Protein ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled
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