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https://www.readbyqxmd.com/read/29081032/prolonged-morphine-treatment-alters-expression-and-plasma-membrane-distribution-of-%C3%AE-adrenergic-receptors-and-some-other-components-of-their-signaling-system-in-rat-cerebral-cortex
#1
Lucie Hejnova, Jitka Skrabalova, Jiri Novotny
β-Adrenergic signaling plays an important role in regulating diverse brain functions and alterations in this signaling have been observed in different neuropathological conditions. In this study, we investigated the effect of a 10-day treatment with high doses of morphine (10 mg/kg per day) on major components and functional state of the β-adrenergic receptor (β-AR) signaling system in the rat cerebral cortex. β-ARs were characterized by radioligand binding assays and amounts of various G protein subunits, adenylyl cyclase (AC) isoforms, G protein-coupled receptor kinases (GRKs), and β-arrestin were examined by Western blot analysis...
October 28, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/29070696/structural-determinants-influencing-the-potency-and-selectivity-of-indazole-paroxetine-hybrid-g-protein-coupled-receptor-kinase-2-inhibitors
#2
Renee Bouley, Helen V Waldschmidt, M Claire Cato, Alessandro Cannavo, Jianliang Song, Joseph Y Cheung, Xin-Qiu Yao, Walter J Koch, Scott D Larsen, John J Tesmer
G protein-coupled receptor kinases (GRKs) phosphorylate activated receptors to promote arrestin binding, decoupling from heterotrimeric G proteins, and internalization. GRK2 and GRK5 are overexpressed in the failing heart and thus have become therapeutic targets. Previously, we discovered two classes of GRK2-selective inhibitors, one stemming from GSK180736A, a ROCK1 inhibitor, and the other from paroxetine, a selective serotonin-reuptake inhibitor. These two classes of compounds bind to the GRK2 active site in a similar configuration, but contain different hinge-binding "warheads": indazole and benzodioxole, respectively...
October 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29054428/%C3%AE-arrestin2-directly-or-through-grk2-inhibits-pkc%C3%AE-ii-activation-in-a-ubiquitination-dependent-manner
#3
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...
October 17, 2017: 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
#4
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...
October 11, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/28882814/opsin-3-and-4-mediate-light-induced-pulmonary-vasorelaxation-that-is-potentiated-by-g-protein-receptor-kinase-2-inhibition
#5
Sebastian Barreto Ortiz, Daijiro Hori, Yohei Nomura, Xin Yun, Haiyang Jiang, Hwanmee Yong, James Chen, Sam Paek, Deepesh Pandey, Gautam Sikka, Anil Bhatta, Andrew Gillard, Jochen Steppan, Jae Hyung Kim, Hideo Adachi, Viachaslau Barodka, Lewis Romer, Steven S An, Larissa A Shimoda, Lakshmi Santhanam, Dan E Berkowitz
We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the non-visual G protein-coupled receptor (GPCR) melanopsin (opsin 4; Opn4). Here we tested the hypothesis that non-visual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G-protein coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2 as demonstrated with a proximity ligation assay...
September 7, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28878120/mdm2-regulates-cardiac-contractility-by-inhibiting-grk2-mediated-desensitization-of-%C3%AE-adrenergic-receptor-signaling
#6
Pierre-Yves Jean-Charles, Samuel Mon-Wei Yu, Dennis Abraham, Reddy Peera Kommaddi, Lan Mao, Ryan T Strachan, Zhu-Shan Zhang, Dawn E Bowles, Leigh Brian, Jonathan A Stiber, Stephen N Jones, Walter J Koch, Howard A Rockman, Sudha K Shenoy
The oncoprotein Mdm2 is a RING domain-containing E3 ubiquitin ligase that ubiquitinates G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2, thereby regulating β-adrenergic receptor (βAR) signaling and endocytosis. Previous studies showed that cardiac Mdm2 expression is critical for controlling p53-dependent apoptosis during early embryonic development, but the role of Mdm2 in the developed adult heart is unknown. We aimed to identify if Mdm2 affects βAR signaling and cardiac function in adult mice...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28843497/long-noncoding-rna-uca1-promotes-tumour-metastasis-by-inducing-grk2-degradation-in-gastric-cancer
#7
Zhen-Qiang Wang, Chang-Yu He, Lei Hu, Hong-Peng Shi, Jian-Fang Li, Qin-Long Gu, Li-Ping Su, Bing-Ya Liu, Chen Li, Zhenggang Zhu
Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) regulate gene and protein expression by exerting an influence on transcriptional and post-transcriptional processes. Here, we report that the lncRNA UCA1 increases the metastatic ability of gastric cancer (GC) cells by regulating GRK2 protein stability by promoting Cbl-c-mediated GRK2 ubiquitination and degradation. This process then activates the ERK-MMP9 signalling pathway. Furthermore, we demonstrate that GRK2 is downregulated in GC cells and that silencing of GRK2 might cause similar phenotypic changes and signalling pathway activation as those induced by elevated UCA1 in GC cells...
November 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28836008/alpha2-adrenoceptors-in-adrenomedullary-chromaffin-cells-functional-role-and-pathophysiological-implications
#8
REVIEW
Antonio R Artalejo, Luis Alcides Olivos-Oré
Chromaffin cells from the adrenal medulla participate in stress responses by releasing catecholamines into the bloodstream. Main control of adrenal catecholamine secretion is exerted both neurally (by the splanchnic nerve fibers) and humorally (by corticosteroids, circulating noradrenaline, etc.). It should be noted, however, that secretory products themselves (catecholamines, ATP, opioids, ascorbic acid, chromogranins) could also influence the secretory response in an autocrine/paracrine manner. This form of control is activity-dependent and can be either inhibitory or excitatory...
August 23, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28818206/pharmacological-and-activated-fibroblast%C3%A2-targeting-of-g%C3%AE-%C3%AE-grk2-after%C3%A2-myocardial-ischemia-attenuates-heart-failure-progression
#9
Joshua G Travers, Fadia A Kamal, Iñigo Valiente-Alandi, Michelle L Nieman, Michelle A Sargent, John N Lorenz, Jeffery D Molkentin, Burns C Blaxall
BACKGROUND: Cardiac fibroblasts are a critical cell population responsible for myocardial extracellular matrix homeostasis. Upon injury or pathological stimulation, these cells transform to an activated myofibroblast state and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation, a hallmark of heart failure (HF), induces pathological signaling through G protein βγ (Gβγ) subunits and their interaction with G protein-coupled receptor kinase 2 (GRK2)...
August 22, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28814745/suppression-of-grk2-expression-reduces-endothelial-dysfunction-by-restoring-glucose-homeostasis
#10
Kumiko Taguchi, Mari Hida, Mami Hasegawa, Haruka Narimatsu, Takayuki Matsumoto, Tsuneo Kobayashi
Despite the associations between diabetic complications and vascular endothelial dysfunction, a direct therapeutic method targeting endothelial dysfunction remains poorly characterized. We have previously shown that chemical inhibition of G-protein-coupled receptor kinase 2 (GRK2) slightly enhances insulin sensitivity and reduces endothelial dysfunction in type 2 diabetic mice. In this study, we identified GRK2 as a novel therapeutic target of diabetic endothelial dysfunction and investigated the effect on diabetic endothelial dysfunction through the systemic administration of GRK2 siRNA using a hydrodynamic-based procedure, resulting in suppression of increased GRK2 protein levels in the liver...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28759639/g-protein-coupled-receptor-kinase-2-promotes-cardiac-hypertrophy
#11
Philipp Schlegel, Julia Reinkober, Eric Meinhardt, Henrike Tscheschner, Erhe Gao, Sarah M Schumacher, Ancai Yuan, Johannes Backs, Patrick Most, Thomas Wieland, Walter J Koch, Hugo A Katus, Philip W Raake
The increase in protein activity and upregulation of G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal heart failure models. The aim of the present study was to investigate the effects of GRK2 on cardiac hypertrophy and dissect potential molecular mechanisms. In mice we observed increased GRK2 mRNA and protein levels following transverse aortic constriction (TAC)...
2017: PloS One
https://www.readbyqxmd.com/read/28711716/impact-of-paroxetine-on-proximal-%C3%AE-adrenergic-receptor-signaling
#12
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
https://www.readbyqxmd.com/read/28699740/design-synthesis-and-evaluation-of-the-highly-selective-and-potent-g-protein-coupled-receptor-kinase-2-grk2-inhibitor-for-the-potential-treatment-of-heart-failure
#13
Tomohiro Okawa, Yoshio Aramaki, Mitsuo Yamamoto, Toshitake Kobayashi, Shoji Fukumoto, Yukio Toyoda, Tsutomu Henta, Akito Hata, Shota Ikeda, Manami Kaneko, Isaac D Hoffman, Bi-Ching Sang, Hua Zou, Tetsuji Kawamoto
A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3...
August 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28653218/2k1c-activated-angiotensin-ii-ang-ii-exacerbates-vascular-damage-in-a-rat-model-of-arthritis-through-the-atr-erk1-2-signaling-pathway
#14
Ying Zhang, Xuexia Luo, Yue Zhou, Huaxun Wu, Jingyu Chen, Ying Wang, Danian Chen, Zhouwei Xu, Shangxue Yan, Wei Wei
OBJECTIVE: To explore the role and mechanism of the two-kidney one-clip (2K1C)-activated Angiotensin II (Ang II) in the development of vascular damage in adjuvant-induced arthritis (AA) rats. METHODS: 2K1C rats were established in normal and AA rats for 35 days. Hypertension, endothelial dysfunction, and vascular hypertrophy induced by 2K1C-activated Ang II in systemic inflammation rats were evaluated. The levels of Ang II and TNF-α in serum were observed by ELISA kits...
June 26, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/28631356/immune-tolerance-effect-in-mesenteric-lymph-node-lymphocytes-of-geniposide-on-adjuvant-arthritis-rats
#15
Zheng-Rong Zhang, Hong Wu, Rong Wang, Shu-Ping Li, Li Dai, Wen-Yu Wang
Rheumatoid arthritis (RA) is a systemic, Th1 cytokine-predominant autoimmune disease result in a chronic and inflammatory disorder. Geniposide (GE), an iridoid glycoside compound that is purified from Gardenia jasminoides Ellis, has antiinflammatory and other immunoregulatory effects, but its exact mechanism of actions on RA is unknown. The aim of this study was to elucidate antiinflammation effects of GE on adjuvant arthritis (AA) rats and its possible immune tolerance mechanisms. Male Sprague-Dawley rats were administered with GE (30, 60, and 120 mg/kg) orally from day 17 to 24 after immunization...
August 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28594409/eif3d-promotes-gallbladder-cancer-development-by-stabilizing-grk2-kinase-and-activating-pi3k-akt-signaling-pathway
#16
Fei Zhang, Shanshan Xiang, Yang Cao, Maolan Li, Qiang Ma, Haibin Liang, Huaifeng Li, Yuanyuan Ye, Yijian Zhang, Lin Jiang, Yunping Hu, Jian Zhou, Xuefeng Wang, Yong Zhang, Lei Nie, Xiao Liang, Wei Gong, Yingbin Liu
Recent evidence suggests that dysregulated eIF3d expression may be critical in various genetic disorders as well as cancer. In this study, we observed that EIF3d levels increased in gallbladder cancer (GBC) samples compared with non-tumor tissue. High eIF3d levels were associated with advanced tumor stage and metastasis and were correlated with poor prognosis in 92 patients with GBC. Depletion of EIF3d in GBC cell lines inhibited cell proliferation, colony formation and metastasis and induced apoptosis and cell cycle arrest in vitro and in vivo...
June 8, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28579429/the-egf-receptor-inhibits-the-signaling-of-dopamine-d3-receptor-through-the-phosphorylation-of-grk2-on-tyrosine-residues
#17
NingNing Sun, Xiaowei Zhang, Xiaohan Zhang, Kyeong-Man Kim
Receptor transactivation or crosstalk are terms referring to instances in which the signaling of a given receptor is regulated by a different class of receptor. The epidermal growth factor (EGF) and the dopaminergic systems in the brain are closely related to schizophrenia with respect to both etiology and treatment. Thus, we investigated the functional interactions between the EGF receptor (EGFR), which belongs to the receptor tyrosine kinase family, and the dopamine D2-like receptors (D2R, D3R, and D4R), which are members of the G protein-coupled receptor (GPCR) family...
August 5, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28572156/g-protein-coupled-receptor-kinase-2-is-a-critical-regulator-of-tnf%C3%AE-signaling-in-colon-epithelial-cells
#18
Michael D Steury, Peter C Lucas, Laura R McCabe, Narayanan Parameswaran
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...
June 27, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28559424/c-x-c-motif-chemokine-receptor-3-splice-variants-differentially-activate-beta-arrestins-to-regulate-downstream-signaling-pathways
#19
Jeffrey S Smith, Priya Alagesan, Nimit K Desai, Thomas F Pack, Jiao-Hui Wu, Asuka Inoue, Neil J Freedman, Sudarshan Rajagopal
Biased agonism, the ability of different ligands for the same receptor to selectively activate some signaling pathways while blocking others, is now an established paradigm for G protein-coupled receptor signaling. One group of receptors in which endogenous bias is critical is the chemokine system, consisting of over 50 ligands and 20 receptors that bind one another with significant promiscuity. We have previously demonstrated that ligands for the same receptor can cause biased signaling responses. The goal of this study was to identify mechanisms that could underlie biased signaling between different receptor splice variants...
August 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28554511/induction-of-cardiac-dysfunction-in-developing-and-adult-zebrafish-by-chronic-isoproterenol-stimulation
#20
Mandy Kossack, Selina Hein, Lonny Juergensen, Mauro Siragusa, Alexander Benz, Hugo A Katus, Patrick Most, David Hassel
Zebrafish is a widely used model to evaluate genetic variants and modifiers that can cause heart muscle diseases. Surprisingly, the β-adrenergic receptor (β-AR) pathway in zebrafish is not well characterized, although abnormal β-AR signaling is a major contributor to human heart failure (HF). Chronic β-AR activation in the attempt to normalize heart function in the failing heart results in a reduction of the β-ARs expression and receptor desensitization, largely mediated through G-protein coupled receptor kinase 2 (GRK2) upregulation...
July 2017: Journal of Molecular and Cellular Cardiology
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