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https://www.readbyqxmd.com/read/29752864/%C3%AE-blockers-interfere-with-cell-homing-receptors-and-regulatory-proteins-in-a-model-of-spontaneously-hypertensive-rats
#1
Bruna Eibel, Melissa Kristochek, Thiago R Peres, Lucinara D Dias, Daniela R Dartora, Karina R Casali, Renato A K Kalil, Alexandre M Lehnen, Maria Claudia Irigoyen, Melissa M Markoski
AIM: To examine the interference of β-blockers with the chemokine stromal cell-derived factor-1 (SDF-1) found in cell homing receptors, C-X-C chemokine receptor type 4 (CXCR-4) and CXCR-7 and regulatory proteins of homing pathways, we administered atenolol, carvedilol, metoprolol and propranolol for 30 days using an orogastric tube to hypertensive rats. METHOD: We collected blood samples before and after treatment and quantified the levels of SDF-1 with enzyme linked immunosorbent assay (ELISA)...
May 12, 2018: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/29739625/gpcrs-and-signal-transducers-interaction-stoichiometry
#2
REVIEW
Vsevolod V Gurevich, Eugenia V Gurevich
Until the late 1990s, class A G protein-coupled receptors (GPCRs) were believed to function as monomers. Indirect evidence that they might internalize or even signal as dimers has emerged, along with proof that class C GPCRs are obligatory dimers. Crystal structures of GPCRs and their much larger binding partners were consistent with the idea that two receptors might engage a single G protein, GRK, or arrestin. However, recent biophysical, biochemical, and structural evidence invariably suggests that a single GPCR binds G proteins, GRKs, and arrestins...
May 5, 2018: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/29698717/inhibition-of-prostatic-smooth-muscle-contraction-by-the-inhibitor-of-g-protein-coupled-receptor-kinase-2-3-cmpd101
#3
Qingfeng Yu, Christian Gratzke, Yiming Wang, Annika Herlemann, Frank Strittmatter, Beata Rutz, Christian G Stief, Martin Hennenberg
Alpha1-adrenoceptors induce prostate smooth muscle contraction, and hold a prominent role for pathophysiology and therapy of lower urinary tract symptoms in benign prostatic hyperplasia. G protein-coupled receptors are regulated by posttranslational regulation, including phosphorylation by G protein-coupled receptor kinases 2 and 3 (GRK2/3). Although posttranslational adrenoceptor regulation has been recently suggested to occur in the prostate, this is still marginally understood. With the newly developed CMPD101, a small molecule with assumed specificity for GRK2/3 is now available...
April 23, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29652832/sympathetic-nerve-hyperactivity-in-the-spleen-causal-for-nonpathogenic-driven-chronic-immune-mediated-inflammatory-diseases-imids
#4
REVIEW
Denise L Bellinger, Dianne Lorton
Immune-Mediated Inflammatory Diseases (IMIDs) is a descriptive term coined for an eclectic group of diseases or conditions that share common inflammatory pathways, and for which there is no definitive etiology. IMIDs affect the elderly most severely, with many older individuals having two or more IMIDs. These diseases include, but are not limited to, type-1 diabetes, obesity, hypertension, chronic pulmonary disease, coronary heart disease, inflammatory bowel disease, and autoimmunity, such as rheumatoid arthritis (RA), Sjőgren's syndrome, systemic lupus erythematosus, psoriasis, psoriatic arthritis, and multiple sclerosis...
April 13, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29627263/utilizing-a-structure-based-docking-approach-to-develop-potent-g-protein-coupled-receptor-kinase-grk-2-and-5-inhibitors
#5
Helen V Waldschmidt, Renee Bouley, Paul D Kirchhoff, Pil Lee, John J G Tesmer, Scott D Larsen
G protein-coupled receptor (GPCR) kinases (GRKs) regulate the desensitization and internalization of GPCRs. Two of these, GRK2 and GRK5, are upregulated in heart failure and are promising targets for heart failure treatment. Although there have been several reports of potent and selective inhibitors of GRK2 there are few for GRK5. Herein, we describe a ligand docking approach utilizing the crystal structures of the GRK2-Gβγ·GSK180736A and GRK5·CCG215022 complexes to search for amide substituents predicted to confer GRK2 and/or GRK5 potency and selectivity...
March 30, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29581292/sortase-ligation-enables-homogeneous-gpcr-phosphorylation-to-reveal-diversity-in-%C3%AE-arrestin-coupling
#6
Dean P Staus, Laura M Wingler, Minjung Choi, Biswaranjan Pani, Aashish Manglik, Andrew C Kruse, Robert J Lefkowitz
The ability of G protein-coupled receptors (GPCRs) to initiate complex cascades of cellular signaling is governed by the sequential coupling of three main transducer proteins, G protein, GPCR kinase (GRK), and β-arrestin. Mounting evidence indicates these transducers all have distinct conformational preferences and binding modes. However, interrogating each transducer's mechanism of interaction with GPCRs has been complicated by the interplay of transducer-mediated signaling events. For example, GRK-mediated receptor phosphorylation recruits and induces conformational changes in β-arrestin, which facilitates coupling to the GPCR transmembrane core...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29570431/g-protein-coupled-receptor-kinase-2-deficient-mice-are-protected-from-dextran-sodium-sulfate-induced-acute-colitis
#7
Michael D Steury, Ho Jun Kang, Taehyung Lee, Peter C Lucas, Laura R McCabe, Narayanan Parameswaran
G-protein coupled receptor kinase 2 (GRK2) is a serine/threonine kinase and plays a key role in different disease processes. Previously, we showed that GRK2 knockdown enhances wound healing in colonic epithelial cells. Therefore, we hypothesized that ablation of GRK2 would protect mice from dextran sodium sulfate (DSS)-induced acute colitis. To test this, we administered DSS to wild-type (GRK2+/+ ) and GRK2 heterozygous (GRK+/- ) mice in their drinking water for 7 days. As predicted, GRK2+/- mice were protected from colitis as demonstrated by decreased weight loss (20% loss in GRK2+/+ vs 11% loss in GRK2+/- ); lower disease activity index (GRK2+/+ 9...
March 23, 2018: Physiological Genomics
https://www.readbyqxmd.com/read/29543709/the-amino-terminal-domain-of-grk5-inhibits-cardiac-hypertrophy-through-the-regulation-of-calcium-calmodulin-dependent-transcription-factors
#8
Daniela Sorriento, Gaetano Santulli, Michele Ciccarelli, Angela Serena Maione, Maddalena Illario, Bruno Trimarco, Guido Iaccarino
We have recently demonstrated that the amino-terminal domain of G protein coupled receptor kinase (GRK) type 5, (GRK5-NT) inhibits NFκB activity in cardiac cells leading to a significant amelioration of LVH. Since GRK5-NT is known to bind calmodulin, this study aimed to evaluate the functional role of GRK5-NT in the regulation of calcium-calmodulin-dependent transcription factors. We found that the overexpression of GRK5-NT in cardiomyoblasts significantly reduced the activation and the nuclear translocation of NFAT and its cofactor GATA-4 in response to phenylephrine (PE)...
March 15, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29535304/functionally-distinct-and-selectively-phosphorylated-gpcr-subpopulations-co-exist-in-a-single-cell
#9
Ao Shen, Madeline Nieves-Cintron, Yawen Deng, Qian Shi, Dhrubajyoti Chowdhury, Jinyi Qi, Johannes W Hell, Manuel F Navedo, Yang K Xiang
G protein-coupled receptors (GPCRs) transduce pleiotropic intracellular signals in a broad range of physiological responses and disease states. Activated GPCRs can undergo agonist-induced phosphorylation by G protein receptor kinases (GRKs) and second messenger-dependent protein kinases such as protein kinase A (PKA). Here, we characterize spatially segregated subpopulations of β2 -adrenergic receptor (β2 AR) undergoing selective phosphorylation by GRKs or PKA in a single cell. GRKs primarily label monomeric β2 ARs that undergo endocytosis, whereas PKA modifies dimeric β2 ARs that remain at the cell surface...
March 13, 2018: Nature Communications
https://www.readbyqxmd.com/read/29530536/g-protein-coupled-receptor-kinase-grk-2-is-a-key-negative-regulator-of-itch-l-glutamine-attenuates-itch-via-a-rapid-induction-of-grk2-in-an-erk-dependent-way
#10
Yu-Na Im, Yu-Dong Lee, Jeong-Soo Park, Hae-Kyoung Kim, Suhn-Young Im, Hwa-Ryung Song, Hern-Ku Lee, Myung-Kwan Han
Many itch mediators activate G-protein coupled receptor (GPCR), and trigger itch via activation of GPCR-mediated signaling pathways. GPCRs are desensitized by G protein-coupled receptor kinases (GRKs). The aim of this study is to explore the role of GRKs in itch response and the linkage between GRKs and glutamine (Gln), an amino acid previously demonstrated as an itching reliever. Itch responses were evoked by histamine, chloroquine (CQ), and dinitrochlorobenzene (DNCB)-induced contact dermatitis (CD). Phosphorylation and protein expression were detected by immunofluorescent staining and Western blotting...
March 9, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29321241/evolution-of-the-shut-off-steps-of-vertebrate-phototransduction
#11
Trevor D Lamb, Hardip R Patel, Aaron Chuah, David M Hunt
Different isoforms of the genes involved in phototransduction are expressed in vertebrate rod and cone photoreceptors, providing a unique example of parallel evolution via gene duplication. In this study, we determine the molecular phylogeny of the proteins underlying the shut-off steps of phototransduction in the agnathan and jawed vertebrate lineages. For the G-protein receptor kinases (GRKs), the GRK1 and GRK7 divisions arose prior to the divergence of tunicates, with further expansion during the two rounds of whole-genome duplication (2R); subsequently, jawed and agnathan vertebrates retained different subsets of three isoforms of GRK...
January 2018: Open Biology
https://www.readbyqxmd.com/read/29054428/%C3%AE-arrestin2-directly-or-through-grk2-inhibits-pkc%C3%AE-ii-activation-in-a-ubiquitination-dependent-manner
#12
Xiaohan Zhang, Mei Zheng, Ningning Sun, Kyeong-Man Kim
The GRK/β-arrestin and PKC/PKA mediate the homologous and heterologous regulation of G protein-coupled receptors (GPCRs), respectively. Interaction between the two pathways is one of the most important issues in understanding the regulation of GPCRs. The present study investigated the regulatory effect of GRK2 and β-arrestins on PKC activation. The roles of GRK2 and β-arrestins in the functional regulation of PKC were assessed by determining their influence on PKC autophosphorylation and intracellular translocation...
January 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29022064/proinflammatory-switch-from-g%C3%AE-s-to-g%C3%AE-i-signaling-by-glucagon-like-peptide-1-receptor-in-murine-splenic-monocyte-following-burn-injury
#13
Qing-Hong Zhang, Ji-Wei Hao, Guang-Lei Li, Xiao-Jing Ji, Xu-Dong Yao, Ning Dong, Yong-Ming Yao
OBJECTIVE: Glucagon-like peptide-1 (GLP-1)-based therapy via G protein-coupled receptor (GPCR) GLP-1R, to attenuate hyperglycemia in critical care has attracted great attention. However, the exaggerated inflammation by GLP-1R agonist, Exendin-4, in a mouse model of burn injury was quite unexpected. Recent studies found that GPCR might elicit proinflammatory effects by switching from Gαs to Gαi signaling in the immune system. Thus, we aimed to investigate the possible Gαs to Gαi switch in GLP-1R signaling in monocyte following burn injury...
February 2018: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/28968826/systemic-and-local-granzyme-b-levels-are-associated-with-disease-activity-kidney-damage-and-interferon-signature-in-systemic-lupus-erythematosus
#14
Helena M Kok, Lucas L van den Hoogen, Joel A G van Roon, Elisabeth J M Adriaansen, Ruth D E Fritsch-Stork, Tri Q Nguyen, Roel Goldschmeding, Timothy R D J Radstake, Niels Bovenschen
Objectives: Granzymes (Grs) are serine proteases that eliminate virally infected or tumour cells by inducing apoptosis. GrB has been shown to be associated to the pathophysiology of SLE, whereas the role of the other Grs in SLE remain unknown. Methods: Gr levels were determined in the serum of SLE patients and controls and linked to SLE activity parameters, including the IFN signature. In addition, GrB expression was investigated in LN biopsies and correlated to kidney function parameters and disease severity...
December 1, 2017: Rheumatology
https://www.readbyqxmd.com/read/28968387/dopamine-negatively-modulates-the-nca-ion-channels-in-c-elegans
#15
Irini Topalidou, Kirsten Cooper, Laura Pereira, Michael Ailion
The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28950947/g-protein-coupled-receptor-kinases-in-the-inflammatory-response-and-signaling
#16
Michael D Steury, Laura R McCabe, Narayanan Parameswaran
G protein-coupled receptor kinases (GRKs) are serine/threonine kinases that regulate a large and diverse class of G protein-coupled receptors (GPCRs). Through GRK phosphorylation and β-arrestin recruitment, GPCRs are desensitized and their signal terminated. Recent work on these kinases has expanded their role from canonical GPCR regulation to include noncanonical regulation of non-GPCR and nonreceptor substrates through phosphorylation as well as via scaffolding functions. Owing to these and other regulatory roles, GRKs have been shown to play a critical role in the outcome of a variety of physiological and pathophysiological processes including chemotaxis, signaling, migration, inflammatory gene expression, etc...
2017: Advances in Immunology
https://www.readbyqxmd.com/read/28893975/agonist-dependent-and-independent-%C3%AE%C2%BA-opioid-receptor-phosphorylation-distinct-phosphorylation-patterns-and-different-cellular-outcomes
#17
Yi-Ting Chiu, Chongguang Chen, Daohai Yu, Stefan Schulz, Lee-Yuan Liu-Chen
We reported previously that the selective agonist U50,488H promoted phosphorylation of the mouse κ opioid receptor (KOPR) at residues S356, T357, T363, and S369. Here, we found that agonist (U50,488H)-dependent KOPR phosphorylation at all the residues was mediated by Gi/o α proteins and multiple protein kinases [GRK2, GRK3, GRK5, GRK6 and protein kinase C (PKC)]. In addition, PKC activation by phorbol ester induced agonist-independent KOPR phosphorylation. Compared with U50,488H, PKC activation promoted much higher S356/T357 phosphorylation, much lower T363 phosphorylation, and similar levels of S369 phosphorylation...
November 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28808053/navigating-the-conformational-landscape-of-g-protein-coupled-receptor-kinases-during-allosteric-activation
#18
COMPARATIVE STUDY
Xin-Qiu Yao, M Claire Cato, Emily Labudde, Tyler S Beyett, John J G Tesmer, Barry J Grant
G protein-coupled receptors (GPCRs) are essential for transferring extracellular signals into carefully choreographed intracellular responses controlling diverse aspects of cell physiology. The duration of GPCR-mediated signaling is primarily regulated via GPCR kinase (GRK)-mediated phosphorylation of activated receptors. Although many GRK structures have been reported, the mechanisms underlying GRK activation are not well-understood, in part because it is unknown how these structures map to the conformational landscape available to this enzyme family...
September 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28711719/g-protein-coupled-receptor-kinases-past-present-and-future
#19
REVIEW
Konstantin E Komolov, Jeffrey L Benovic
This review is provided in recognition of the extensive contributions of Dr. Robert J. Lefkowitz to the G protein-coupled receptor (GPCR) field and to celebrate his 75th birthday. Since one of the authors trained with Bob in the 80s, we provide a history of work done in the Lefkowitz lab during the 80s that focused on dissecting the mechanisms that regulate GPCR signaling, with a particular emphasis on the GPCR kinases (GRKs). In addition, we highlight structure/function characteristics of GRK interaction with GPCRs as well as a review of two recent reports that provide a molecular model for GRK-GPCR interaction...
January 2018: Cellular Signalling
https://www.readbyqxmd.com/read/28711716/impact-of-paroxetine-on-proximal-%C3%AE-adrenergic-receptor-signaling
#20
Shuchi Guo, Rhonda L Carter, Laurel A Grisanti, Walter J Koch, Douglas G Tilley
β-adrenergic receptors (βAR) regulate numerous functions throughout the body, however G protein-coupled receptor kinase (GRK)-dependent desensitization of βAR has long been recognized as a maladaptive process in the progression of various disease states. Thus, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was identified as a GRK2 inhibitor that enhances βAR-dependent cardiomyocyte and cardiac contractility and reverses cardiac dysfunction and myocardial βAR expression in mouse models of heart failure...
October 2017: Cellular Signalling
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