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https://www.readbyqxmd.com/read/28711716/impact-of-paroxetine-on-proximal-%C3%AE-adrenergic-receptor-signaling
#1
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...
July 12, 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
#2
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 towards GRK2, and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, 7 with almost equipotent inhibition to GRK3...
July 12, 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
#3
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
#4
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...
June 19, 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
#5
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
#6
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...
June 1, 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
#7
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
#8
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 GPCR 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...
May 30, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28554511/induction-of-cardiac-dysfunction-in-developing-and-adult-zebrafish-by-chronic-isoproterenol-stimulation
#9
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...
May 26, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28526706/cardiac-hyporesponsiveness-in-severe-sepsis-is-associated-with-nitric-oxide-dependent-activation-of-g-protein-receptor-kinase
#10
Daniela Dal-Secco, Silvia DalBó, Natalia E S Lautherbach, Fábio N Gava, Mara R N Celes, Patricia O Benedet, Adriana H Souza, Juliana Akinaga, Vanessa Lima, Katiussia P Silva, Luiz Ricardo A Kiguti, Marcos A Rossi, Isis C Kettelhut, André S Pupo, Fernando Q Cunha, Jamil Assreuy
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)...
July 1, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28483024/preliminary-analysis-of-parkinson-like-motor-coordination-abnormityin-brain-specific-hs100b-transgenic-mice
#11
Jialin Liu, Fang Zheng, Yan Long, Liu Tong, Yuan Zheng, Xiaoqing Liu, Chuan Qin
Objective To investigate the role of S100B in the development of Parkinson's disease (PD) and explore the possibility of brain-specific S100B transgenic mice as PD animal model. Methods The hS100B transgenic mice were established. The mice were divided into S100B transgenic group (TG),S100B knockout group (KG),and the non-transgenic control group (CG). Motor coordination ability of mice was measured by the rota-rod and pole-climbing test. The expressions of S100B,dopamine D1 receptor,dopamine D2 receptor,G protein-coupled receptor kinase (GRK)2,GRK5,and tyrosine hydroxylase in brain tissue were detected by reverse transcription-polymerase chain reaction and Western blot...
April 20, 2017: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae
https://www.readbyqxmd.com/read/28429504/induced-pluripotent-stem-cells-reduce-neutrophil-chemotaxis-via-activating-grk2-in-endotoxin-induced-acute-lung-injury
#12
Vincent Yi-Fong Su, Shih-Hwa Chiou, Chi-Shiuan Lin, Wei-Chih Chen, Wen-Kuang Yu, Yen-Wen Chen, Cheng-Yu Chen, Kuang-Yao Yang
BACKGROUND AND OBJECTIVE: We investigated the effect of induced pluripotent stem cells (iPSCs) in moderating neutrophil chemotaxis in endotoxin-induced acute lung injury (ALI). METHODS: Male C57BL/6 mice at 8-12 weeks of age were studied. Murine iPSCs were delivered through the tail veins of mice 4 h after intratracheal instillation of endotoxin. Lung histopathological findings, neutrophil counts in peripheral blood and bronchoalveolar lavage fluid (BALF), bone marrow (BM) cell distribution, expression of chemokine receptors and regulatory signalling pathways were analysed after 24 h...
August 2017: Respirology: Official Journal of the Asian Pacific Society of Respirology
https://www.readbyqxmd.com/read/28389415/g-protein-coupled-receptor-kinase-2-grk2-as-an-integrative-signalling-node-in-the-regulation-of-cardiovascular-function-and-metabolic-homeostasis
#13
REVIEW
Federico Mayor, Marta Cruces-Sande, Alba C Arcones, Rocío Vila-Bedmar, Ana M Briones, Mercedes Salaices, Cristina Murga
G protein-coupled receptor kinase 2 (GRK2) is emerging as a pivotal signalling hub able to integrate different transduction cascades. This ability appears to underlie its central role in different physiological and pathological conditions. Key mediators of cardiovascular function (such as catecholamines or angiotensin II) and components of the systemic milieu altered in insulin resistance conditions converge in increasing GRK2 levels in diverse cardiovascular cell types. In turn, GRK2 would simultaneously modulate several cardiovascular regulatory pathways, including GPCR and insulin signalling cascades, NO bioavailability and mitochondrial function...
April 4, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28381559/identification-of-a-signaling-cascade-that-maintains-constitutive-%C3%AE-opioid-receptor-incompetence-in-peripheral-sensory-neurons
#14
Allison Doyle Brackley, Shayda Sarrami, Ruben Gomez, Kristi A Guerrero, Nathaniel A Jeske
μ-Opioid receptor (MOR) agonists are often used to treat severe pain but can result in adverse side effects. To circumvent systemic side effects, targeting peripheral opioid receptors is an attractive alternative treatment for severe pain. Activation of the δ-opioid receptor (DOR) produces similar analgesia with reduced side effects. However, until primed by inflammation, peripheral DOR is analgesically incompetent, raising interest in the mechanism. We recently identified a novel role for G-protein-coupled receptor kinase 2 (GRK2) that renders DOR analgesically incompetent at the plasma membrane...
May 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28381182/involvement-of-mir-125a-in-resistance-to-daunorubicin-by-inhibiting-apoptosis-in-leukemia-cell-lines
#15
Haitao Bai, Lili Zhou, Chun Wang, Xiaowei Xu, Jieling Jiang, Youwen Qin, Xiaorui Wang, Chuxian Zhao, Shan Shao
In this study, we investigated whether miR-125a participated in the resistance of the leukemia cell lines to the chemotherapeutic agent daunorubicin. Higher expression of miR-125a is correlated with lower treatment response and shorter overall survival in acute leukemia patients. Overexpression of miR-125a induced drug resistance in HL-60, K562, and THP-1cell lines through reducing apoptosis. We also showed that miR-125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRK2 and Puma which were proved to be direct targets of miR-125a...
April 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28349925/paroxetine-alleviates-t-lymphocyte-activation-and-infiltration-to-joints-of-collagen-induced-arthritis
#16
Qingtong Wang, Longsheng Wang, Li Wu, Mei Zhang, Shanshan Hu, Rui Wang, Yongsheng Han, Yujing Wu, Lingling Zhang, Xinming Wang, Wuyi Sun, Wei Wei
T cell infiltration to synovial tissue is an early pathogenic mechanism of rheumatoid arthritis (RA). In the present work, we reveal that G protein coupled receptor kinase 2 (GRK2) is abundantly expressed in T cells of collagen-induced arthritis (CIA). A GRK2 inhibitor, paroxetine protects the joints from inflammation and destruction, primarily through inhibition of both CD4(+) helper T (Th) cell and CD8(+) cytotoxic T (Tc) cell migration to synovial tissue. Meanwhile, paroxetine restores the balance of Th/Tc, effector Th (Theff)/ naïve Th (Thnaive) and effector Tc (Tceff)/ naïve Tc (Tcnaive) to equilibrium by elevating the frequency of Thnaive, Tcnaive and regulatory Th cells; reducing the increased Theff, activated Th and Tceff, having a similar effect as methotrexate (MTX)...
March 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28331048/g-protein-coupled-receptor-kinase-3-and-protein-kinase-c-phosphorylate-the-distal-c-terminal-tail-of-the-chemokine-receptor-cxcr4-and-mediate-recruitment-of-%C3%AE-arrestin
#17
Jiansong Luo, John M Busillo, Ralf Stumm, Jeffrey L Benovic
Phosphorylation of G protein-coupled receptors (GPCRs) is a key event for cell signaling and regulation of receptor function. Previously, using tandem mass spectrometry, we identified two phosphorylation sites at the distal C-terminal tail of the chemokine receptor CXCR4, but were unable to determine which specific residues were phosphorylated. Here, we demonstrate that serines (Ser) 346 and/or 347 (Ser-346/7) of CXCR4 are phosphorylated upon stimulation with the agonist CXCL12 as well as a CXCR4 pepducin, ATI-2341...
June 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28328744/non-canonical-roles-of-grks-in-cardiovascular-signaling
#18
Sarah M Schumacher, Walter J Koch
G protein-coupled receptor kinases (GRKs) are classically known for their role in regulating the activity of the largest known class of membrane receptors, which influence diverse biological processes in every cell type in the human body. As researchers have tried to uncover how this family of kinases, containing only 7 members, achieves selective and coordinated control of receptors, they have uncovered a growing number of non-canonical activities for these kinases. These activities include phosphorylation of non-receptor targets and kinase-independent molecular interactions...
March 17, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28323425/structure-based-design-of-highly-selective-and-potent-g-protein-coupled-receptor-kinase-2-inhibitors-based-on-paroxetine
#19
Helen V Waldschmidt, Kristoff T Homan, Marilyn C Cato, Osvaldo Cruz-Rodríguez, Alessandro Cannavo, Michael W Wilson, Jianliang Song, Joseph Y Cheung, Walter J Koch, John J G Tesmer, Scott D Larsen
In heart failure, the β-adrenergic receptors (βARs) become desensitized and uncoupled from heterotrimeric G proteins. This process is initiated by G protein-coupled receptor kinases (GRKs), some of which are upregulated in the failing heart, making them desirable therapeutic targets. The selective serotonin reuptake inhibitor, paroxetine, was previously identified as a GRK2 inhibitor. Utilizing a structure-based drug design approach, we modified paroxetine to generate a small compound library. Included in this series is a highly potent and selective GRK2 inhibitor, 14as, with an IC50 of 30 nM against GRK2 and greater than 230-fold selectivity over other GRKs and kinases...
April 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28315953/the-influence-of-tnf-%C3%AE-and-ang-ii-on-the-proliferation-migration-and-invasion-of-hepg2-cells-by-regulating-the-expression-of-grk2
#20
Zhou-Wei Xu, Shang-Xue Yan, Hua-Xun Wu, Jing-Yu Chen, Ying Zhang, Ying Li, Wei Wei
PURPOSE: Hepatocellular carcinoma (HCC) is a common digestive system malignancy that is associated with a poor prognosis. This study researched the interaction of tumor necrosis factor-α (TNF-α) and angiotensin II (Ang II) in HCC cells proliferation, migration and invasion and examined their influence on the expression of G protein-coupled receptor kinase 2 (GRK2) and relevant receptors. METHODS: Cell Counting Kit-8 and Transwell assays were performed to evaluate the effects of TNF-α and Ang II on HepG2 cells proliferation, migration and invasion...
April 2017: Cancer Chemotherapy and Pharmacology
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