DOCSLIB.ORG

Inflammation Regulator of Lymphocyte Homing and LPA Axis Emerges As

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

The Autotaxin−LPA Axis Emerges as a Novel Regulator of Lymphocyte Homing and Inflammation This information is current as Sara Knowlden and Steve N. Georas of September 27, 2021. J Immunol 2014; 192:851-857; ; doi: 10.4049/jimmunol.1302831 http://www.jimmunol.org/content/192/3/851 Downloaded from References This article cites 79 articles, 35 of which you can access for free at: http://www.jimmunol.org/content/192/3/851.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology The Autotaxin–LPA Axis Emerges as a Novel Regulator of Lymphocyte Homing and Inflammation Sara Knowlden* and Steve N. Georas*,† Lysophosphatidic acid (LPA) is a pleiotropic lipid mol- but not saturated (16:0 and 18:0), LPA (2), possibly ecule with potent effects on cell growth and motility. reflecting affinity for the cell surface receptor LPA3 (see Major progress has been made in recent years in deci- below). phering the mechanisms of LPA generation and how it LPA can be generated by multiple mechanisms, and a cur- acts on target cells. Most research has been conducted in rent challenge in the field is to relate different potential sources other disciplines, but emerging data indicate that LPA of LPA to biological activities in vivo. Extracellular LPA is has an important role to play in immunity. A key dis- thought to derive from at least two pathways. First, LPA can covery was that autotaxin (ATX), an enzyme previously be produced by the action of phospholipases on membrane Downloaded from implicated in cancer cell motility, generates extracellular microvesicles shed by activated platelets and erythrocytes (1, 3, 4). LPA from the precursor lysophosphatidylcholine. Steady- These pathways involve the direct hydrolysis of a fatty acid state ATX is expressed by only a few tissues, including moiety from membrane-derived phosphatidic acid. Second, high endothelial venules in lymph nodes, but inflamma- LPA can be generated from lysophosphatidylcholine (LPC) tory signals can upregulate ATX expression in differ- by removal of the choline moiety by the enzyme lysophospho- http://www.jimmunol.org/ ent tissues. In this article, we review current thinking lipase D (lyso-PLD). LPC is an intermediate in multiple lipid about the ATX/LPA axis in lymphocyte homing, as well metabolic pathways and circulates in the blood stream at a as in models of allergic airway inflammation and much higher concentration than LPA (5). These two pathways asthma. New insights into the role of LPA in regulating are not mutually exclusive, because certain phospholipases can produce LPC and other lysophospholipids from acti- immune responses should be forthcoming in the near vated platelets that are then cleaved by lyso-PLD to produce future. The Journal of Immunology, 2014, 192: LPA (4). 851–857. In 2002, the dominant lyso-PLD in serum was found to be an enzyme known as autotaxin (ATX) (6, 7). ATX had been by guest on September 27, 2021 discovered 10 years earlier by Liotta and colleagues (8), who Nomenclature and LPA generation were studying autocrine factors that promoted cancer cell ysophosphatidic acid (LPA) is a member of the gly- motility. Cloning of the autotaxin cDNA revealed domains cerophospholipid family, specifically a monoacylgly- similar to the ectonucleotide phosphodiesterase and pyro- L cerophosphate (GP1005, according to Lipid Maps phosphatase family, and ATX was designated ENPP2 (9). classification; http://www.lipidmaps.org). LPA has a three- However, the preferred substrates for ATX are not nucleotides carbon glycerol backbone with one acyl side chain that can but actually lysophospholipids, including LPC (4), and it is vary in length and saturation (Fig. 1). The prefix “lyso” indicates becoming clear that many functions previously ascribed to that only one fatty acid is attached to the phospholipid back- ATX can be explained by its ability to generate LPA. This is bone, and it distinguishes LPA from phosphatidic acid. The acyl especially true in the field of cancer biology, where the ATX/ group is usually located on the sn-1 carbon (i.e., 1-acyl-2- LPA axis is involved in the growth and metastasis of many hydroxy-sn-glycero-3-phosphate). In serum, most LPA species different tumors, and pathway antagonists are under active are polyunsaturated (e.g., 18:2 and 20:4) or monounsaturated development (10). (e.g., 18:1) (1). Emerging data indicate that the acyl moiety LPA is unstable in plasma, with a half-life , 5min,and affects the function of LPA, but this is a virtually unexplored area technically challenging to measure (11, 12). Experiments using in the immune system. One exception is the observation that lipid phosphate phosphatase (LPP)1 hypomorphic mice revealed immature mouse bone marrow–derived dendritic cells (DCs) that this enzyme is a major determinant of LPA instability preferentially migrate in vitro to unsaturated (18:1 and 20:4), in vivo (11). Interestingly, there appear to be tissue-specific *Department of Microbiology and Immunology, University of Rochester Medical Center, Abbreviations used in this article: ATX, autotaxin; BAL, bronchoalveolar lavage; DC, Rochester, NY 14642; and †Division of Pulmonary and Critical Care Medicine, Depart- dendritic cell; EC, endothelial cell; GPCR, G protein–coupled receptor; HEV, high ment of Medicine, University of Rochester Medical Center, Rochester, NY 14642 endothelial venule; LPA, lysophosphatidic acid; LPC, lysophosphatidylcholine; LPP, lipid phosphate phosphatase; lyso-PLD, lysophospholipase D; MS, mass spectrometry; Received for publication October 23, 2013. Accepted for publication December 5, 2013. S1P, sphingosine-1 phosphate. This work was supported by National Institutes of Health Grants R01 HL071933 and P30 ES001247 (to S.N.G.) and T32 AI007285 (to S.K.). Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 Address correspondence and reprint requests to Dr. Steve N. Georas, University of Rochester Medical Center, 601 Elmwood Avenue, Box 692, Rochester, NY 14642. E-mail address: [email protected] www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302831 852 BRIEF REVIEWS: ATX/LPA REGULATE LYMPHOCYTE HOMING AND INFLAMMATION Downloaded from http://www.jimmunol.org/ FIGURE 1. Two main sources of LPA generation are from phosphatidic acid (left) via the action of phospholipases or by hydrolysis of the choline moiety of lysophosphatidylcholine (Lyso-PC), by ATX (also known as Lyso-PLD). Newly generated LPA can act on cell surface GPCRs or intracellular receptors, as indicated. Free LPA is rapidly degraded by lipid phosphate phosphatases into monoacyl glycerol. differences in LPP expression and activity, suggesting that ex- and other proteins, and it seems likely that this restricts its by guest on September 27, 2021 tracellularLPAmaybemorestableinsometissuesthanothers interaction with target receptors. (11). Relatively little is known about the stability of LPA in secondary lymphoid organs, although LPP expression is rela- LPA binds to different cell surface receptors and intracellular targets tively high in the spleen. The discovery that LPA interacted with specific cell surface LPA can be measured by colorimetric assays or mass receptors was a major advance. A detailed discussion of LPA spectrometry (MS), which has the advantage of detecting receptors is beyond the scope of this Brief Review, but this specific acyl side chains. A typical approach involves lipid topic was summarized recently (16). There are at least six G extraction, followed by HPLC and tandem MS in negative ion protein–coupled receptors (GPCR) that bind LPA and vary in mode, monitoring for the glycerol phosphoryl moiety (m/z = their tissue distribution. LPA1 (Edg2), LPA2 (Edg4), and 152.9) and parent compound acyl groups. To estimate LPA LPA3 (Edg7) belong to the Edg family, whereas LPA4–6 are concentrations, a closely related LPA species not normally more closely related to cell surface purinergic receptors (16, 17). present should be spiked into the original sample, extracted Other Edg receptor family members bind sphingosine-1 phos- and processed identically, and used to generate a standard phate (S1P), including S1P1 (Edg2). Signal transduction via curve. However, the efficiency of extraction of different LPA LPA receptors leads to activation of MAPKs, PI3K, and Rho species varies based on the sample and method used; at present, kinases, which affect cell activation, survival, and migration. the true bioactive concentrations of LPA in plasma or bio- This is a rapidly evolving field in which new candidate logical fluids is not clear. Plasma concentrations are probably receptors are being actively pursued; however, the lack of Abs inthe100-nMrangeandarehigherinwomenthaninmen directed against extracellular domains that detect surface ex- (5, 13, 14). In mice, similar variability in plasma LPA con- pression or antagonize LPA binding is a major hindrance. The centrations has been reported, reflecting the poorly under- availability of LPA receptor–deficient mice is starting to stood effects of age, gender, and strain (11). provide insights into the function of this molecule in vivo The function of circulating extracellular LPA is not known. (18), although more research is needed in models of innate Because the kDa of cell surface LPA receptors is in the nM and adaptive immunity.
Recommended publications
  • CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

    CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma

    International Journal of Molecular Sciences Article CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma 1, 2,3,4, 5 6 7 Ju-Fang Liu y, Chiang-Wen Lee y, Chih-Yang Lin , Chia-Chia Chao , Tsung-Ming Chang , Chien-Kuo Han 8, Yuan-Li Huang 8, Yi-Chin Fong 9,10,* and Chih-Hsin Tang 8,11,12,* 1 School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei City 11031, Taiwan; [email protected] 2 Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Puzi City, Chiayi County 61363, Taiwan; [email protected] 3 Department of Nursing, Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Puzi City, Chiayi County 61363, Taiwan 4 Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Guishan Dist., Taoyuan City 33303, Taiwan 5 School of Medicine, China Medical University, Taichung 40402, Taiwan; [email protected] 6 Department of Respiratory Therapy, Fu Jen Catholic University, New Taipei City 24205, Taiwan; [email protected] 7 School of Medicine, Institute of Physiology, National Yang-Ming University, Taipei City 11221, Taiwan; [email protected] 8 Department of Biotechnology, College of Health Science, Asia University, Taichung 40402, Taiwan; [email protected] (C.-K.H.); [email protected] (Y.-L.H.) 9 Department of Sports Medicine, College of Health Care, China Medical University, Taichung 40402, Taiwan 10 Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin 65152, Taiwan 11 Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan 12 Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan * Correspondence: [email protected] (Y.-C.F.); [email protected] (C.-H.T.); Tel.: +886-4-2205-2121-7726 (C.-H.T.); Fax: +886-4-2233-3641 (C.-H.T.) These authors contributed equally to this work.
  • Synthesis of Lysophospholipids

    Synthesis of Lysophospholipids

    Molecules 2010, 15, 1354-1377; doi:10.3390/molecules15031354 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Synthesis of Lysophospholipids Paola D’Arrigo 1,2,* and Stefano Servi 1,2 1 Dipartimento di Chimica, Materiali ed Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy 2 Centro Interuniversitario di Ricerca in Biotecnologie Proteiche "The Protein Factory", Politecnico di Milano and Università degli Studi dell'Insubria, Via Mancinelli 7, 20131 Milano, Italy * Author to whom correspondence should be addressed; E-Mail: paola.d’[email protected]. Received: 17 February 2010; in revised form: 4 March 2010 / Accepted: 5 March 2010 / Published: 8 March 2010 Abstract: New synthetic methods for the preparation of biologically active phospholipids and lysophospholipids (LPLs) are very important in solving problems of membrane–chemistry and biochemistry. Traditionally considered just as second-messenger molecules regulating intracellular signalling pathways, LPLs have recently shown to be involved in many physiological and pathological processes such as inflammation, reproduction, angiogenesis, tumorogenesis, atherosclerosis and nervous system regulation. Elucidation of the mechanistic details involved in the enzymological, cell-biological and membrane-biophysical roles of LPLs relies obviously on the availability of structurally diverse compounds. A variety of chemical and enzymatic routes have been reported in the literature for the synthesis of LPLs: the enzymatic transformation of natural glycerophospholipids (GPLs) using regiospecific enzymes such as phospholipases A1 (PLA1), A2 (PLA2) phospholipase D (PLD) and different lipases, the coupling of enzymatic processes with chemical transformations, the complete chemical synthesis of LPLs starting from glycerol or derivatives. In this review, chemo- enzymatic procedures leading to 1- and 2-LPLs will be described.
  • Lysophosphatidic Acids and Their Substrate Lysophospholipids In

    Lysophosphatidic Acids and Their Substrate Lysophospholipids In

    www.nature.com/scientificreports OPEN Lysophosphatidic acids and their substrate lysophospholipids in cerebrospinal fuid as objective Received: 5 October 2018 Accepted: 14 June 2019 biomarkers for evaluating the Published: xx xx xxxx severity of lumbar spinal stenosis Kentaro Hayakawa1, Makoto Kurano2, Junichi Ohya1, Takeshi Oichi1, Kuniyuki Kano3, Masako Nishikawa2, Baasanjav Uranbileg2, Ken Kuwajima4, Masahiko Sumitani4,5, Sakae Tanaka1, Junken Aoki 3, Yutaka Yatomi2 & Hirotaka Chikuda6 Lysophospholipids (LPLs) are known to have potentially important roles in the initiation and maintenance of neuropathic pain in animal models. This study investigated the association between the clinical severity of lumbar spinal stenosis (LSS) and the cerebrospinal fuid (CSF) levels of LPLs, using human samples. We prospectively identifed twenty-eight patients with LSS and ffteen controls with idiopathic scoliosis or bladder cancer without neurological symptoms. We quantifed LPLs from CSF using liquid chromatography-tandem mass spectrometry. We assessed clinical outcome measures of LSS (Neuropathic Pain Symptom Inventory (NPSI) and Zurich Claudication Questionnaire (ZCQ)) and categorized patients into two groups according to their severity. Five species of lysophosphatidic acid (LPA), nine species of lysophosphatidylcholine (LPC), and one species of lysophosphatidylinositol (LPI) were detected. The CSF levels of all species of LPLs were signifcantly higher in LSS patients than controls. Patients in the severe NPSI group had signifcantly higher LPL levels (three species of LPA and nine species of LPC) than the mild group. Patients in the severe ZCQ group also had signifcantly higher LPL levels (four species of LPA and nine species of LPC). This investigation demonstrates a positive correlation between the CSF levels of LPLs and the clinical severity of LSS.
  • G-Protein-Coupled Receptor Signaling and Polarized Actin Dynamics Drive

    G-Protein-Coupled Receptor Signaling and Polarized Actin Dynamics Drive

    RESEARCH ARTICLE elifesciences.org G-protein-coupled receptor signaling and polarized actin dynamics drive cell-in-cell invasion Vladimir Purvanov, Manuel Holst, Jameel Khan, Christian Baarlink, Robert Grosse* Institute of Pharmacology, University of Marburg, Marburg, Germany Abstract Homotypic or entotic cell-in-cell invasion is an integrin-independent process observed in carcinoma cells exposed during conditions of low adhesion such as in exudates of malignant disease. Although active cell-in-cell invasion depends on RhoA and actin, the precise mechanism as well as the underlying actin structures and assembly factors driving the process are unknown. Furthermore, whether specific cell surface receptors trigger entotic invasion in a signal-dependent fashion has not been investigated. In this study, we identify the G-protein-coupled LPA receptor 2 (LPAR2) as a signal transducer specifically required for the actively invading cell during entosis. We find that 12/13G and PDZ-RhoGEF are required for entotic invasion, which is driven by blebbing and a uropod-like actin structure at the rear of the invading cell. Finally, we provide evidence for an involvement of the RhoA-regulated formin Dia1 for entosis downstream of LPAR2. Thus, we delineate a signaling process that regulates actin dynamics during cell-in-cell invasion. DOI: 10.7554/eLife.02786.001 Introduction Entosis has been described as a specialized form of homotypic cell-in-cell invasion in which one cell actively crawls into another (Overholtzer et al., 2007). Frequently, this occurs between tumor cells such as breast, cervical, or colon carcinoma cells and can be triggered by matrix detachment (Overholtzer et al., 2007), suggesting that loss of integrin-mediated adhesion may promote cell-in-cell invasion.
  • G-Protein-Coupled Receptor Heteromer Dynamics

    G-Protein-Coupled Receptor Heteromer Dynamics

    Commentary 4215 G-protein-coupled receptor heteromer dynamics Jean-Pierre Vilardaga1,2,*, Luigi F. Agnati3, Kjell Fuxe4 and Francisco Ciruela5 1Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA 2Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA 3IRCCS, San Camillo, Lido Venezia, Italy 4Department of Neuroscience, Karolinska Institute, Stockholm SE-17177, Sweden 5Pharmacology Unit, Department of Pathology and Experimental Therapy, Faculty of Medicine, University of Barcelona, 08907 Barcelona, Spain *Author for correspondence ([email protected]) Journal of Cell Science 123, 000-000 © 2010. Published by The Company of Biologists Ltd doi:10.1242/jcs.063354 Summary G-protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors, and have evolved to detect and transmit a large palette of extracellular chemical and sensory signals into cells. Activated receptors catalyze the activation of heterotrimeric G proteins, which modulate the propagation of second messenger molecules and the activity of ion channels. Classically thought to signal as monomers, different GPCRs often pair up with each other as homo- and heterodimers, which have been shown to modulate signaling to G proteins. Here, we discuss recent advances in GPCR heteromer systems involving the kinetics of the early steps in GPCR signal transduction, the dynamic property of receptor–receptor interactions, and how the formation of receptor heteromers modulate the kinetics of G-protein signaling. Key words: G-protein-coupled receptors, Heterodimers, Signaling Introduction the signaling and trafficking mechanisms of GPCRs is thus central G-protein-coupled receptors (GPCRs) constitute the main family for the development of new and safer therapies for many of cell surface receptors for a large variety of chemical stimuli physiological and psychological disorders.
  • G Protein-Coupled Receptors: What a Difference a ‘Partner’ Makes

    G Protein-Coupled Receptors: What a Difference a ‘Partner’ Makes

    Int. J. Mol. Sci. 2014, 15, 1112-1142; doi:10.3390/ijms15011112 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review G Protein-Coupled Receptors: What a Difference a ‘Partner’ Makes Benoît T. Roux 1 and Graeme S. Cottrell 2,* 1 Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK; E-Mail: [email protected] 2 Reading School of Pharmacy, University of Reading, Reading RG6 6UB, UK * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +44-118-378-7027; Fax: +44-118-378-4703. Received: 4 December 2013; in revised form: 20 December 2013 / Accepted: 8 January 2014 / Published: 16 January 2014 Abstract: G protein-coupled receptors (GPCRs) are important cell signaling mediators, involved in essential physiological processes. GPCRs respond to a wide variety of ligands from light to large macromolecules, including hormones and small peptides. Unfortunately, mutations and dysregulation of GPCRs that induce a loss of function or alter expression can lead to disorders that are sometimes lethal. Therefore, the expression, trafficking, signaling and desensitization of GPCRs must be tightly regulated by different cellular systems to prevent disease. Although there is substantial knowledge regarding the mechanisms that regulate the desensitization and down-regulation of GPCRs, less is known about the mechanisms that regulate the trafficking and cell-surface expression of newly synthesized GPCRs. More recently, there is accumulating evidence that suggests certain GPCRs are able to interact with specific proteins that can completely change their fate and function. These interactions add on another level of regulation and flexibility between different tissue/cell-types.
  • Interleukin-21 in Immunity and Autoimmunity

    Interleukin-21 in Immunity and Autoimmunity

    Interleukin-21 in immunity and autoimmunity Alexis Vogelzang A thesis submitted for the degree of Doctor of Philosophy in the Faculty of Medicine, University of New South Wales Mucosal Autoimmunity Unit, Garvan Institute of Medical Research Sydney, Australia Awarded September 2010 1 ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Alexis Vogelzang Date …………………………………………….............. 2 COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation.
  • Fingolimod Rescues Demyelination in a Mouse Model of Krabbe's Disease

    Fingolimod Rescues Demyelination in a Mouse Model of Krabbe's Disease

    Research Articles: Neurobiology of Disease Fingolimod rescues demyelination in a mouse model of Krabbe's disease https://doi.org/10.1523/JNEUROSCI.2346-19.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.2346-19.2020 Received: 30 September 2019 Revised: 17 December 2019 Accepted: 21 January 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 Be´chet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Fingolimod rescues demyelination in a mouse model of Krabbe’s disease 2 Sibylle Béchet, Sinead O’Sullivan, Justin Yssel, Steven G. Fagan, Kumlesh K. Dev 3 Drug Development, School of Medicine, Trinity College Dublin, IRELAND 4 5 Corresponding author: Prof. Kumlesh K. Dev 6 Corresponding author’s address: Drug Development, School of Medicine, Trinity College 7 Dublin, IRELAND, D02 R590 8 Corresponding author’s phone and fax: Tel: +353 1 896 4180 9 Corresponding author’s e-mail address: [email protected] 10 11 Number of pages: 35 pages 12 Number of figures: 9 figures 13 Number of words (Abstract): 216 words 14 Number of words (Introduction): 641 words 15 Number of words (Discussion): 1475 words 16 17 Abbreviated title: Investigating the use of FTY720 in Krabbe’s disease 18 19 Acknowledgement statement (including conflict of interest and funding sources): This work 20 was supported, in part, by Trinity College Dublin, Ireland and the Health Research Board, 21 Ireland.
  • Direct Coupling of Detergent Purified Human Mglu5 Receptor To

    Direct Coupling of Detergent Purified Human Mglu5 Receptor To

    www.nature.com/scientificreports OPEN Direct coupling of detergent purifed human mGlu5 receptor to the heterotrimeric G proteins Gq Received: 24 July 2017 Accepted: 26 February 2018 and Gs Published: xx xx xxxx Chady Nasrallah1, Karine Rottier1, Romain Marcellin1, Vincent Compan1, Joan Font2, Amadeu Llebaria 2, Jean-Philippe Pin 1, Jean-Louis Banères3 & Guillaume Lebon1 The metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) that modulate synaptic activity and plasticity throughout the mammalian brain. Signal transduction is initiated by glutamate binding to the venus fytrap domains (VFT), which initiates a conformational change that is transmitted to the conserved heptahelical domains (7TM) and results ultimately in the activation of intracellular G proteins. While both mGlu1 and mGlu5 activate Gαq G-proteins, they also increase intracellular cAMP concentration through an unknown mechanism. To study directly the G protein coupling properties of the human mGlu5 receptor homodimer, we purifed the full-length receptor, which required careful optimisation of the expression, N-glycosylation and purifcation. We successfully purifed functional mGlu5 that activated the heterotrimeric G protein Gq. The high- afnity agonist-PAM VU0424465 also activated the purifed receptor in the absence of an orthosteric agonist. In addition, it was found that purifed mGlu5 was capable of activating the G protein Gs either upon stimulation with VU0424465 or glutamate, although the later induced a much weaker response. Our fndings provide important mechanistic insights into mGlu5 G protein-dependent activity and selectivity. Te metabotropic glutamate (mGlu) receptors belong to class C of the large family of G protein-coupled receptors (GPCRs). mGlu receptors are localized to both synaptic and extra-synaptic sites in neurons and glia where they modulate the strength of synaptic transmission by sensing the extracellular concentration of glutamate.
  • The Role of Fatty Acids in Ceramide Pathways and Their Influence On

    The Role of Fatty Acids in Ceramide Pathways and Their Influence On

    International Journal of Molecular Sciences Review The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review Andressa Reginato 1,2,3,*, Alana Carolina Costa Veras 2,3, Mayara da Nóbrega Baqueiro 2,3, Carolina Panzarin 2,3, Beatriz Piatezzi Siqueira 2,3, Marciane Milanski 2,3 , Patrícia Cristina Lisboa 1 and Adriana Souza Torsoni 2,3,* 1 Biology Institute, State University of Rio de Janeiro, UERJ, Rio de Janeiro 20551-030, Brazil; [email protected] 2 Faculty of Applied Science, University of Campinas, UNICAMP, Campinas 13484-350, Brazil; [email protected] (A.C.C.V.); [email protected] (M.d.N.B.); [email protected] (C.P.); [email protected] (B.P.S.); [email protected] (M.M.) 3 Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas 13083-864, Brazil * Correspondence: [email protected] (A.R.); [email protected] (A.S.T.) Abstract: Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy Citation: Reginato, A.; Veras, A.C.C.; balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition Baqueiro, M.d.N.; Panzarin, C.; to targets for the development of new drugs that can be used in humans to decrease body weight.
  • The Role of Lipids in the Inception, Maintenance and Complications of Dengue Virus Infection

    The Role of Lipids in the Inception, Maintenance and Complications of Dengue Virus Infection

    www.nature.com/scientificreports OPEN The role of lipids in the inception, maintenance and complications of dengue virus infection Received: 12 April 2018 Carlos Fernando Odir Rodrigues Melo 1, Jeany Delafori1, Mohamad Ziad Dabaja1, Accepted: 25 June 2018 Diogo Noin de Oliveira1, Tatiane Melina Guerreiro1, Tatiana Elias Colombo2, Published: xx xx xxxx Maurício Lacerda Nogueira 2, Jose Luiz Proenca-Modena3 & Rodrigo Ramos Catharino1 Dengue fever is a viral condition that has become a recurrent issue for public health in tropical countries, common endemic areas. Although viral structure and composition have been widely studied, the infection phenotype in terms of small molecules remains poorly established. This contribution providing a comprehensive overview of the metabolic implications of the virus-host interaction using a lipidomic- based approach through direct-infusion high-resolution mass spectrometry. Our results provide further evidence that lipids are part of both the immune response upon Dengue virus infection and viral infection maintenance mechanism in the organism. Furthermore, the species described herein provide evidence that such lipids may be part of the mechanism that leads to blood-related complications such as hemorrhagic fever, the severe form of the disease. Dengue virus (DENV) is an arbovirus transmitted by mosquitoes of the genus Aedes, such as Aedes aegypti and Aedes albopictus. DENV is associated with outbursts of febrile diseases in the tropics since the 80’s1. Te large number of DENV-infected patients every year, estimated by the World Health Organization in 390 million, makes DENV the most hazardous arbovirus in the world. DENV is a series of enveloped viruses belonging to the family Flaviviridae, genus Flavivirus, which are classifed in four closely related and antigenically distinct serotypes (DENV-1, DENV-2, DENV-3 and DENV-4).
  • Phytosphingosine-1-Phosphate Stimulates Chemotactic Migration of L2071 Mouse Fibroblasts Via Pertussis Toxin-Sensitive G-Proteins

    Phytosphingosine-1-Phosphate Stimulates Chemotactic Migration of L2071 Mouse Fibroblasts Via Pertussis Toxin-Sensitive G-Proteins

    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 39, No. 2, 185-194, April 2007 Phytosphingosine-1-phosphate stimulates chemotactic migration of L2071 mouse fibroblasts via pertussis toxin-sensitive G-proteins 1,2 1 Mi-Kyoung Kim , Kyoung Sun Park , demonstrates that PhS1P stimulates at least two 3 3 Hyuck Lee , Young Dae Kim , different signaling cascades, one is a PTX-insensi- 1,2 1,2,4 Jeanho Yun and Yoe-Sik Bae tive but phospholipase C dependent intracellular calcium increase, and the other is a PTX-sensitive 1 Medical Research Center for Cancer Molecular Therapy chemotactic migration mediated by phosphoino - 2 Department of Biochemistry sitide 3-kinase and p38 kinase. 3 Department of Internal Medicine Keywords: calcium signaling; chemotaxis; fibroblasts; College of Medicine, Dong-A University GTP-binding proteins; pertussis toxin; phytosphingo- Busan 602-714, Korea 4 sine-1-phosphate Corresponding author: Tel, 82-51-240-2889; Fax, 82-51-241-6940; E-mail, [email protected] Introduction Accepted 9 February 2007 Many reports have demonstrated the involvement of Abbreviations: BAPTA/AM, 1,2-bis (Aminophenoxy) ethane-N,N,N’,N’- 2+ lipid factors in cellular responses. In particular, tetraacetoxymethyl ester; [Ca ]i, intracellular calcium concentration; sphingosine-1-phosphate (S1P) and lysophosphati- GPCRs, G-protein coupled receptors; IP3, inositol-1,4,5-trisphos- dic acid (LPA) are important lipid mediators, which phate; LPA, lysophosphatidic acid; PD98059, 2’-amino-3’-meth- modulate a wide range of physiological activities oxyflavone; PhS1P, phytosphingosine-1-phosphate; PI3K, phosphati- (van Corven et al., 1989; English et al., 1999; Wang dylinositol-3-kinase; PTX, pertussis toxin; LY294002, 2-(4-Mor- et al., 1999; Fishman et al., 2001; Cummings et al., pholinyl)-8-phenyl-4H-1-benzopyran-4-one; S1P, sphingosine-1- 2002; Idzko et al., 2002; Kim et al., 2004).