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GRK2

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https://www.readbyqxmd.com/read/29733383/pde4-and-makap%C3%AE-are-nodal-organizers-of-%C3%AE-2-ars-nuclear-pka-signaling-in-cardiac-myocytes
#1
Ibrahim Bedioune, Florence Lefebvre, Patrick Lechêne, Audrey Varin, Valérie Domergue, Michael S Kapiloff, Rodolphe Fischmeister, Grégoire Vandecasteele
Aims: β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. Methods and Results: We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation...
May 3, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29698717/inhibition-of-prostatic-smooth-muscle-contraction-by-the-inhibitor-of-g-protein-coupled-receptor-kinase-2-3-cmpd101
#2
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/29675711/%C3%AE-2-adrenoceptor-signaling-reduction-is-involved-in-the-inflammatory-response-of-fibroblast-like-synoviocytes-from-adjuvant-induced-arthritic-rats
#3
Huaxun Wu, Jingyu Chen, Chun Wang, Lihua Liu, Yujing Wu, Yunfang Zhang, Aiwu Zhou, Lingling Zhang, Wei Wei
OBJECTIVE: To investigate the effects of β-AR signaling on fibroblast-like synoviocytes (FLS) from adjuvant-induced arthritis (AA) rats and the partial mechanisms focused on β-AR desensitization mediated by GRK2 and β-arrestin2. METHODS: Animals were divided into a control group and an AA model group, and FLSs were cultured. Arthritis index, histopathology of joints, epinephrine (Epi) and norepinephrine (NE) were detected in vivo. The effect of the β-AR agonist isoprenaline (ISO) and the β2 -AR agonist salbutamol on FLS cell viability were detected by CCK8...
April 19, 2018: Inflammopharmacology
https://www.readbyqxmd.com/read/29628461/-molecular-mechanism-for-et-1-induced-insulin-resistance-in-skeletal-muscle-cells
#4
Takahiro Horinouchi, Yuichi Mazaki, Koji Terada, Soichi Miwa
Insulin resistance is a condition where the sensitivity to insulin of the tissues expressing insulin receptor (InsR) is decreased due to a functional disturbance of InsR-mediated intracellular signaling. Insulin promotes the entry of glucose into the tissues and skeletal muscle is the most important tissue responsible for the insulin's action of decreasing blood glucose levels. Endothelin-1 (ET-1), a potent vasoconstrictor and pro-inflammatory peptide, induces insulin resistance through a direct action on skeletal muscle...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
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/29570431/g-protein-coupled-receptor-kinase-2-deficient-mice-are-protected-from-dextran-sodium-sulfate-induced-acute-colitis
#6
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/29551601/different-phosphorylation-patterns-regulate-%C3%AE-1d-adrenoceptor-signaling-and-desensitization
#7
Marco A Alfonzo-Méndez, Gabriel Carmona-Rosas, David A Hernández-Espinosa, M Teresa Romero-Ávila, J Adolfo García-Sáinz
Human α1D -adrenoceptors (α1D -ARs) are a group of the seven transmembrane-spanning proteins that mediate many of the physiological and pathophysiological actions of adrenaline and noradrenaline. Although it is known that α1D -ARs are phosphoproteins, their specific phosphorylation sites and the kinases involved in their phosphorylation remain largely unknown. Using a combination of in silico analysis, mass spectrometry and site directed mutagenesis, we identified distinct α1D -AR phosphorylation patterns during noradrenaline- or phorbol ester-mediated desensitizations...
March 15, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29531822/grk2-moderates-the-acute-mitochondrial-damage-to-ionizing-radiation-exposure-by-promoting-mitochondrial-fission-fusion
#8
Antonietta Franco, Daniela Sorriento, Jessica Gambardella, Roberto Pacelli, Nella Prevete, Claudio Procaccini, Giuseppe Matarese, Bruno Trimarco, Guido Iaccarino, Michele Ciccarelli
The modern understanding of the G protein-coupled receptor kinase 2 has grown towards the definition of a stress protein, for its ability to rapidly compartmentalize within the cell in response to acute stimulation. Also, mitochondria can be regulated by GRK2 localization. We show that Ionizing Radiation (IR) exposure acutely damages mitochondria regarding mass, morphology, and respiration, with recovery in a framework of hours. This phenomenon is actively regulated by GRK2, whose overexpression results to be protective, and reciprocally, deletion accelerates degenerative processes...
December 2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29530536/gpcr-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
#9
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 GPCR and trigger itch via activation of GPCR-mediated signaling pathways. GPCRs are desensitized by GPCR kinases (GRKs). The aim of this study is to explore the role of GRKs in itch response and the link between GRKs and glutamine, an amino acid previously shown to be an itch reliever. Itch responses were evoked by histamine, chloroquine, and dinitrochlorobenzene-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/29500815/role-of-g-protein-coupled-receptor-kinase-2-in-oxidative-and-nitrosative-stress-related-neurohistopathological-changes-in-a-mouse-model-of-sepsis-associated-encephalopathy
#10
Masaaki Kawakami, Mizuki Hattori, Wakana Ohashi, Toshio Fujimori, Kohshi Hattori, Mariko Takebe, Kengo Tomita, Hiroki Yokoo, Naoyuki Matsuda, Mitsuaki Yamazaki, Yuichi Hattori
Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-G protein-coupled receptor-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE...
March 3, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29487132/the-dopamine-d2-receptor-can-directly-recruit-and-activate-grk2-without-g-protein-activation
#11
Thomas F Pack, Margo I Orlen, Caroline Ray, Sean M Peterson, Marc G Caron
The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is critical for many central nervous system functions. The D2R carries out these functions by signaling through two transducers: G proteins and β-arrestins (βarrs). Selectively engaging either the G protein or βarr pathway may be a way to improve drugs targeting GPCRs. The current model of GPCR signal transduction posits a chain of events where G protein activation ultimately leads to βarr recruitment. GPCR kinases (GRKs), which are regulated by G proteins and whose kinase action facilitates βarr recruitment, bridge these pathways...
April 20, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29473135/immunomodulatory-effects-of-cp-25-on-splenic-t-cells-of-rats-with-adjuvant-arthritis
#12
Yang Wang, Chen-Chen Han, Dongqian Cui, Ting-Ting Luo, Yifan Li, Yuwen Zhang, Yang Ma, Wei Wei
Rheumatoid arthritis (RA) is an autoimmune disease in which T cells play an important role. Paeoniflorin-6-oxy-benzenesulfonate (CP-25) shows a strong anti-inflammatory and immunomodulatory effect in the joint of adjuvant arthritis (AA) rats, but the role of the spleen function is still unclear. The aim of this study was to research how CP-25 regulated spleen function of AA rats. Male Sprague-Dawley rats were administered with CP-25 (50 mg/kg) orally from day 17 to 29 after immunization. The spleen histopathological changes were analyzed by hematoxylin-eosin staining...
February 23, 2018: Inflammation
https://www.readbyqxmd.com/read/29463871/co-treatment-with-clonidine-and-a-grk2-inhibitor-prevented-rebound-hypertension-and-endothelial-dysfunction-after-withdrawal-in-diabetes
#13
Kumiko Taguchi, Nanami Bessho, Mami Hasegawa, Haruka Narimatsu, Takayuki Matsumoto, Tsuneo Kobayashi
Hypertension and diabetes are associated with a risk of cardiovascular disease. Clonidine is currently used as a fourth-line drug therapy for hypertension because of its rebound hypertensive effect and short half-life. The purpose of this study was to investigate the combined effect of an antihypertensive drug (clonidine) and a G-protein-coupled receptor kinase 2 (GRK2) inhibitor on rebound hypertension and endothelial dysfunction. The clonidine and/or GRK2 inhibitor were administered by continuous infusion for 14 days by using an osmotic pump that was implanted subcutaneously...
April 2018: Hypertension Research: Official Journal of the Japanese Society of Hypertension
https://www.readbyqxmd.com/read/29442133/follicle-stimulating-hormone-enhances-hepatic-gluconeogenesis-by-grk2-mediated-ampk-hyperphosphorylation-at-ser485-in-mice
#14
Xiaoyi Qi, Yanjing Guo, Yongfeng Song, Chunxiao Yu, Lifang Zhao, Li Fang, Dehuan Kong, Jiajun Zhao, Ling Gao
AIMS/HYPOTHESIS: Increased serum follicle-stimulating hormone (FSH) is correlated with fasting hyperglycaemia. However, the underlying mechanism remains unclear. Because excessive hepatic gluconeogenesis is a major cause of fasting hyperglycaemia the present study investigated whether FSH increases hepatic gluconeogenesis in mice. METHODS: Ovariectomised mice supplemented with oestradiol (E2) to maintain normal levels of serum E2 (OVX+E2 mice) were injected with low or high doses of FSH...
May 2018: Diabetologia
https://www.readbyqxmd.com/read/29402362/-effects-of-mild-hypothermia-on-%C3%AE-adrenergic-signaling-pathway-in-a-cardiac-arrest-swine-model
#15
Fangfang Zhu, Xianfei Ji, Xia Zhong, Haoran Hu, Lining Liang, Jibin Chen, Deya Shang
OBJECTIVE: To observe the effect of mild hypothermia on myocardial β-adrenergic receptor (β-AR) signal pathway after cardiopulmonary resuscitation (CPR) in pigs with cardiac arrest (CA) and explore the mechanism of myocardial protection. METHODS: Healthy male Landraces were collected for reproducing the CA-CPR model (after 8-minute untreated ventricular fibrillation, CPR was implemented). The animals were divided into two groups according to random number table (n = 8)...
February 2018: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue
https://www.readbyqxmd.com/read/29363585/biased-signaling-by-thyroid-stimulating-hormone-receptor-specific-antibodies-determines-thyrocyte-survival-in-autoimmunity
#16
Syed A Morshed, Risheng Ma, Rauf Latif, Terry F Davies
The thyroid-stimulating hormone receptor (TSHR) is a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR). Autoimmune hyperthyroidism, commonly known as Graves' disease (GD), is caused by stimulating autoantibodies to the TSHR. We previously described TSHR-specific antibodies (TSHR-Abs) in GD that recognize linear epitopes in the cleavage region of the TSHR ectodomain (C-TSHR-Abs) and induce thyroid cell apoptosis instead of stimulating the TSHR. We found that C-TSHR-Abs entered the cell through clathrin-mediated endocytosis but did not trigger endosomal maturation and failed to undergo normal vesicular sorting and trafficking...
January 23, 2018: Science Signaling
https://www.readbyqxmd.com/read/29247373/-epigallocatechin-3-gallate-the-major-green-tea-catechin-regulates-the-desensitization-of-%C3%AE-1-adrenoceptor-via-grk2-in-experimental-heart-failure
#17
Qi Zhang, Liqun Hu, Li Chen, Hongqi Li, Jun Wu, Wenting Liu, Mengyuan Zhang, Guang Yan
OBJECTIVE: We investigated the effect of (-)-epigallocatechin-3-gallate (EGCG) on cardiac function and its mechanism, which focused on the desensitization of β1-AR and GRK2 in heart failure (HF) rats. METHODS: HF was induced by abdominal aortic coarctation. Four weeks after HF induction, the rats were given EGCG (25, 50, 100 mg/kg/day). Cardiac function was assessed by measuring haemodynamic parameters. Histological changes were analyzed by HE and Masson's trichrome staining...
December 16, 2017: Inflammopharmacology
https://www.readbyqxmd.com/read/29212811/altered-expression-of-hepatic-%C3%AE-adrenergic-receptors-in-aging-rats-implications-for-age-related-metabolic-dysfunction-in-liver
#18
Yun Shi, Zhen-Ju Shu, Hanzhou Wang, Jeffrey L Barnes, Chih-Ko Yeh, Paramita M Ghosh, Michael S Katz, Amrita Kamat
Increased β-adrenergic receptor (β-AR)-mediated activation of adenylyl cyclase (AC) in rat liver during aging has been linked to age-related increases in hepatic glucose output and hepatosteatosis. In this study we investigated the expression of β-ARs, individual receptor subtypes, and G protein-coupled receptor (GPCR) regulatory proteins in livers from aging rats. Radioligand binding studies demonstrated that β-AR density increased by >3-fold in hepatocyte membranes from senescent (24 mo old) compared to young adult (7 mo old) rats, and that this phenomenon was blocked by food restriction which is known to retard aging processes in rodents...
December 6, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29166798/grk2-as-a-therapeutic-target-for-heart-failure
#19
REVIEW
Alessandro Cannavo, Klara Komici, Leonardo Bencivenga, Maria Loreta D'amico, Giuseppina Gambino, Daniela Liccardo, Nicola Ferrara, Giuseppe Rengo
G protein-coupled receptor (GPCR) kinase-2 (GRK2) is a regulator of GPCRs, in particular β-adrenergic receptors (ARs), and as demonstrated by decades of investigation, it has a pivotal role in the development and progression of cardiovascular disease, like heart failure (HF). Indeed elevated levels and activity of this kinase are able to promote the dysfunction of both cardiac and adrenal α- and β-ARs and to dysregulate other protective signaling pathway, such as sphingosine 1-phospate and insulin. Moreover, recent discoveries suggest that GRK2 can signal independently from GPCRs, in a 'non-canonical' manner, via interaction with non-GPCR molecule or via its mitochondrial localization...
January 2018: Expert Opinion on Therapeutic Targets
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
#20
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...
December 2017: Journal of Molecular Neuroscience: MN
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