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Jie-Jie Sun, Hui-Ting Yang, Guo-Juan Niu, Xiao-Wu Feng, Jiang-Feng Lan, Xiao-Fan Zhao, Jin-Xing Wang
Impaired phosphatase activity leads to the persistent activation of signal transducers and activators of transcription (Stat). In mammals, Stat family members are often phosphorylated or dephosphorylated by the same enzymes. To date, only one Stat similar to mammalian Stat5a/b has been found in crustaceans and there have been few studies in Stat signal regulation in crustaceans. Here, we report that β-arrestin1 interacts with TC45 (45-kDa form of T cell protein tyrosine phosphatase) in the nucleus to attenuate Stat signaling by promoting dephosphorylation of Stat...
October 26, 2016: Scientific Reports
Federica Ferrari, Maria Camilla Cerlesi, Davide Malfacini, Laila Asth, Elaine C Gavioli, Velvet B Journigan, Uma G Kamakolanu, Michael E Meyer, Dennis Yasuda, Willma E Polgar, Anna Rizzi, Remo Guerrini, Chiara Ruzza, Nurulain T Zaveri, Girolamo Calo
Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in receptor binding and [(35)S]GTPγS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays...
October 22, 2016: European Journal of Pharmacology
Muhammad Rafehi, Joachim C Burbiel, Isaac Y Attah, Aliaa Abdelrahman, Christa E Müller
The Gq protein-coupled, ATP- and UTP-activated P2Y2 receptor is a potential drug target for a range of different disorders, including tumor metastasis, inflammation, atherosclerosis, kidney disorders, and osteoporosis, but pharmacological studies are impeded by the limited availability of suitable antagonists. One of the most potent and selective antagonists is the thiouracil derivative AR-C118925. However, this compound was until recently not commercially available and little is known about its properties...
October 20, 2016: Purinergic Signalling
Wu-Yi Sun, Shan-Shan Hu, Jing-Jing Wu, Qiong Huang, Yang Ma, Qing-Tong Wang, Jing-Yu Chen, Wei Wei
β-arrestins, including β-arrestin1 and β-arrestin2, are multifunctional adaptor proteins. β-arrestins have recently been found to play new roles in regulating intracellular signalling networks associated with malignant cell functions. Altered β-arrestin expression has been reported in many cancers, but its role in hepatocellular carcinoma (HCC) is not clear. We therefore examined the roles of β-arrestins in HCC using an animal model of progressive HCC, HCC patient samples and HCC cell lines with stepwise metastatic potential...
October 19, 2016: Scientific Reports
Jingyu Yao, Lin Jia, Kecia Feathers, Chengmao Lin, Naheed W Khan, Daniel J Klionsky, Thomas A Ferguson, David N Zacks
Autophagy is a lysosomal degradation pathway critical to preventing the accumulation of cytotoxic proteins. Deletion of the essential autophagy gene Atg5 from the rod photoreceptors of the retina (atg5(Δrod) mouse) results in the accumulation of the phototransduction protein transducin and the degeneration of these neurons. The purpose of this study is to test the hypothesis that autophagic degradation of visual transduction proteins prevents retinal degeneration. Targeted deletion of both Gnat1 (a gene encoding the alpha subunit of the heterotrimeric G-protein transducin) and Atg5 in the rod photoreceptors resulted in a significantly decreased rate of rod cell degeneration as compared to the atg5(Δrod) mouse retina, and considerable preservation of photoreceptors...
October 18, 2016: Autophagy
D A Bangasser, H Dong, J Carroll, Z Plona, H Ding, L Rodriguez, C McKennan, J G Csernansky, S H Seeholzer, R J Valentino
Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than in men. Corticotropin-releasing factor (CRF) orchestrates the stress response, and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF1 receptor (CRF1) is sex biased whereby coupling to its GTP-binding protein, Gs, is greater in females, whereas β-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing (CRF-OE) mice to test the proof of principle that when CRF is in excess, sex-biased CRF1 coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles...
October 18, 2016: Molecular Psychiatry
S Lieb, T Littmann, N Plank, J Felixberger, M Tanaka, T Schäfer, S Krief, S Elz, K Friedland, G Bernhardt, J Wegener, T Ozawa, A Buschauer
A set of histamine H1 receptor (H1R) agonists and antagonists was characterized in functional assays, using dynamic mass redistribution (DMR), electric cell-substrate impedance sensing (ECIS) and various signaling pathway specific readouts (Fura-2 and aequorin calcium assays, arrestin recruitment (luciferase fragment complementation) assay, luciferase gene reporter assay). Data were gained from genetically engineered HEK293T cells and compared with reference data from GTPase assays and radioligand binding. Histamine and the other H1R agonists gave different assay-related pEC50 values, however, the order of potency was maintained...
October 14, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Tyler A Johnson, Laura Milan-Lobo, Tao Che, Madeline Ferwerda, Eptisam Lambo, Nicole L McIntosh, Fei Li, Li He, Nicholas Lorig-Roach, Phillip Crews, Jennifer Lynne Whistler
Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin® (4), Vicodin® (5) and Dilaudid® (6) are "biased" agonists at the µ opioid receptor (OR), wherein they engage G-protein signaling but poorly engage β-arrestin and the endocytic machinery. In contrast, the endorphins, met-enkephalin (14) and β-endorphin (15), endogenous peptide agonists for ORs, are more potent analgesics then 1, show reduced liability for tolerance and dependence, and engage both G-protein and β-arrestin pathways as "balanced" agonists...
October 17, 2016: ACS Chemical Neuroscience
Jianjun Cheng, John D McCorvy, Patrick M Giguère, Hu Zhu, Terry Kenakin, Bryan L Roth, Alan P Kozikowski
Based on the structural similarity of our previous 5-HT2C agonists with the melatonin receptor agonist tasimelteon, and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5-HT2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment...
October 11, 2016: Journal of Medicinal Chemistry
Olivier De Henau, Gaetan-Nagim Degroot, Virginie Imbault, Virginie Robert, Cédric De Poorter, Saria Mcheik, Céline Galés, Marc Parmentier, Jean-Yves Springael
Chemerin is a small chemotactic protein originally identified as the natural ligand of CMKLR1. More recently, two other receptors, GPR1 and CCRL2, have been reported to bind chemerin but their functional relevance remains poorly understood. In this study, we compared the binding and signaling properties of the three human chemerin receptors and showed differences in mode of chemerin binding and receptor signaling. Chemerin binds to all three receptors with low nanomolar affinities. However, the contribution of the chemerin C-terminus to binding efficiency varies greatly amongst receptors...
2016: PloS One
Paul J Cocker, M Tremblay, S Kaur, Catharine A Winstanley
RATIONALE: Whilst dopamine agonist therapies can successfully manage the symptoms of diseases such as Parkinson's disease (PD), fibromyalgia and restless leg syndrome, they can also cause impulse control and addiction disorders such as gambling disorder (GD). These compulsive behaviours seriously undermine the utility of such treatments. OBJECTIVES: The objective of the study was to model this phenomenon using a rodent slot machine task (rSMT) in order to investigate the neurobiological basis underlying such behavioural changes...
October 6, 2016: Psychopharmacology
Ségolène Galandrin, Colette Denis, Cédric Boularan, Jacky Marie, Céline M'Kadmi, Claire Pilette, Caroline Dubroca, Yvan Nicaise, Marie-Hélène Seguelas, Du N'Guyen, Jean-Louis Banères, Atul Pathak, Jean-Michel Sénard, Céline Galés
Hyperactivity of the renin-angiotensin-aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin-angiotensin-aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown...
October 3, 2016: Hypertension
Arpita Sen, Ligia Acosta-Sampson, Christopher G Alvaro, Jonathan S Ahn, Jamie H D Cate, Jeremy Thorner
: When expressed in Saccharomyces cerevisiae using either of two constitutive yeast promoters (PGK1prom and CCW12prom), the transporters CDT-1 and CDT-2 from the filamentous fungus Neurospora crassa are able to catalyze, respectively, active transport and facilitated diffusion of cellobiose (and, for CDT-2, also xylan and its derivatives). In S. cerevisiae, endogenous permeases are removed from the plasma membrane by clathrin-mediated endocytosis and are marked for internalization through ubiquitinylation catalyzed by Rsp5, a HECT class ubiquitin:protein ligase (E3)...
September 30, 2016: Applied and Environmental Microbiology
Stephen W Bickler, Eliel Lizardo, David M Cauvi, Antonio De Maio
Urbanization in Africa is associated with an increased incidence of non-communicable diseases, yet the cause and the mechanism remain poorly understood. Here, we propose a role for G protein-coupled receptor (GPCR) signaling in the biological changes that occur with urbanization and suggest a critical area of convergence in GPCR signaling might provide a molecular signature for exposure to environmental factors. As a first step in investing this hypothesis, we examined the expression of the G protein α, β and γ subunit, G protein related kinase, and β-arrestin genes in a rural and urban population living in Morocco (NCBI GSE8847)...
October 2016: Medical Hypotheses
Anna Bagnato, Laura Rosanò
Metastatization is a complex multistep process requiring fine-tuned regulated cytoskeleton re-modeling, mediated by the cross-talk of actin with interacting partners, such as the Rho GTPases. Our expanding knowledge of invadopodia, small invasive membrane protrusions composed of a core of F-actin, actin regulators and actin-binding proteins, and hotspots for secretion of extracellular matrix (ECM) proteinases, contributes to clarify critical steps of the metastatic program. Growth factor receptors and their intermediate signaling molecules, along with matrix adhesion and rigidity, pH and hypoxia, act as drivers of cytoskeleton changes and invadopodia formation...
October 3, 2016: Small GTPases
Bo Dong, Xiaojin Xu, Guoqing Chen, Dandan Zhang, Mingzhi Tang, Fei Xu, Xiaohong Liu, Hua Wang, Bo Zhou
No abstract text is available yet for this article.
September 30, 2016: Scientific Reports
Byron Carpenter, Christopher G Tate
G protein-coupled receptors (GPCRs) modulate cytoplasmic signalling in response to extracellular stimuli, and are important therapeutic targets in a wide range of diseases. Structure determination of GPCRs in all activation states is important to elucidate the precise mechanism of signal transduction and to facilitate optimal drug design. However, due to their inherent instability, crystallisation of GPCRs in complex with cytoplasmic signalling proteins, such as heterotrimeric G proteins and β-arrestins, has proved challenging...
September 26, 2016: Protein Engineering, Design & Selection: PEDS
Shauna L Houlihan, Alison A Lanctot, Yan Guo, Yuanyi Feng
Neuronal fate-restricted intermediate progenitors (IPs) are derived from the multipotent radial glia (RGs) and serve as the direct precursors for cerebral cortical neurons, but factors that control their neurogenic plasticity remain elusive. Here we report that IPs' neuron production is enhanced by abrogating filamin function, leading to the generation of periventricular neurons independent of normal neocortical neurogenesis and neuronal migration. Loss of Flna in neural progenitor cells (NPCs) led RGs to undergo changes resembling epithelial-mesenchymal transition (EMT) along with exuberant angiogenesis that together changed the microenvironment and increased neurogenesis of IPs...
September 24, 2016: ELife
Laura C Sullivan, Teresa A Chavera, Raehannah J Jamshidi, Kelly A Berg, William P Clarke
Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions, however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a non-responsive state to a functionally competent state. Here we tested the hypothesis that the basal, non-responsive state of the mu and delta opioid receptors (MOR and DOR, respectively) is the result of constitutive receptor activity that activates desensitization mechanisms, resulting in MOR and DOR receptor systems that are constitutively desensitized...
September 22, 2016: Journal of Pharmacology and Experimental Therapeutics
Katie A McCrink, Ava Brill, Malika Jafferjee, Thairy Reyes Valero, Christine Marrero, Martha M Rodriguez, Genevieve M Hale, Anastasios Lymperopoulos
AIM: The β1-adrenergic receptor (AR) Arg389Gly polymorphism affects efficacy of its procontractile signaling in cardiomyocytes and carriers' responses to β-blockers. To identify molecular mechanisms underlying functional differences between Arg389 and Gly389 β1ARs, we examined their binding to β-arrestins (βarr-1 and -2), which mediate β1AR signaling, in neonatal rat ventricular myocytes. METHODS: We tested the β1AR-βarr interaction via β1AR immunoprecipitation followed by βarr immunoblotting...
October 2016: Pharmacogenomics
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