DOCSLIB.ORG

The Role of G Protein-Coupled Receptors in Lymphoid Malignancies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of G Protein-Coupled Receptors in Lymphoid Malignancies Accepted Manuscript The role of G protein-coupled receptors in lymphoid malignancies Adrienne Nugent, Richard L. Proia PII: S0898-6568(17)30218-8 DOI: doi: 10.1016/j.cellsig.2017.08.002 Reference: CLS 8973 To appear in: Cellular Signalling Received date: 25 May 2017 Revised date: 4 August 2017 Accepted date: 7 August 2017 Please cite this article as: Adrienne Nugent, Richard L. Proia , The role of G protein- coupled receptors in lymphoid malignancies, Cellular Signalling (2017), doi: 10.1016/ j.cellsig.2017.08.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Title: The role of G protein-coupled receptors in lymphoid malignancies Adrienne Nugent and Richard L. Proia National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA; [email protected] and [email protected] Address correspondence to: Richard L. Proia, PhD NIH/NIDDK 10 Center Drive, Bethesda, MD, 20892, USA (301) 496-4391 [email protected] Disclosure of conflicts of interest: None Author contributions: AN conceptualized, wrote and edited the review; RLP conceptualized and edited the review. All authors have approved the final article. ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT ABSTRACT: B cell lymphoma consists of multiple individual diseases arising throughout the lifespan of B cell development. From pro-B cells in the bone marrow, through circulating mature memory B cells, each stage of B cell development is prone to oncogenic mutation and transformation, which can lead to a corresponding lymphoma. Therapies designed against individual types of lymphoma often target features that differ between malignant cells and the corresponding normal cells from which they arise. These genetic changes between tumor and normal cells can include oncogene activation, tumor suppressor gene repression and modified cell surface receptor expression. G protein-coupled receptors (GPCRs) are an important class of cell surface receptors that represent an ideal target for lymphoma therapeutics. GPCRs bind a wide range of ligands to relay extracellular signals through G protein-mediated signaling cascades. Each lymphoma subgroup expresses a unique pattern of GPCRs and efforts are underway to fully characterize these patterns at the genetic level. Aberrations such as overexpression, deletion and mutation of GPCRs have been characterized as having causative roles in lymphoma and such studies describing GPCRs in B cell lymphomas are summarized here. Keywords: GPCR; lymphoma; cancer; mutation; chemokine receptors; lipid receptors ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Abbreviations: ABC = Activated B cell-like ALL = Acute lymphoblastic leukemia ATP = Adenosine triphosphate B-ALL = B cell acute lymphoblastic leukemia BCR = B cell receptor BL = Burkitt lymphoma BLR1 = Burkitt lymphoma receptor 1 cAMP = Cyclic adenosine monophosphate CCND1 = Cyclin D1 CLL = Chronic lymphocytic leukemia CREB = Cyclic adenosine monophosphate response element-binding protein CRLF2 = Cytokine receptor like factor 2 DLBCL = Diffuse large B cell lymphoma DLBCL-NOS = Diffuse large B cell lymphoma-not otherwise specified EBI2 = Epstein-Barr virus-induced G protein-coupled receptor 2 FL = Follicular lymphoma GCB = Germinal center B cell-like GPCR = G protein-coupled receptor HCL = Hairy cell leukemia IGHV = Immunoglobulin heavy-chain variable region gene IgM = Immunoglobulin M IHC = Immunohistochemistry JNK = c-Jun N-terminal kinase LPA = Lysophosphatidic acid LPL = Lymphoplasmacytic lymphoma MALT = Mucosa-associated lymphoid tissue MAML2 = Mastermind like transcriptional coactivator 2 MAPK = Mitogen-activated protein kinase MCL = Mantle cell lymphoma MFI = Mean or median fluorescence intensity MGUS = Monoclonal gammopathy of undetermined significance MMP-9 = Matrix metallopeptidase 9 MZL = Marginal zone lymphoma NF-κB = Nuclear factor-kappa B NHL = Non-Hodgkin’s lymphoma PMBCL = Primary mediastinal large B-cell lymphoma S1P = SphingosineACCEPTED-1-phosphate MANUSCRIPT SLL = Small lymphocytic lymphoma T-ALL = T cell acute lymphoblastic leukemia TFH = Follicular helper T cell Treg = Regulatory T cell VEGF = Vascular endothelial growth factor VLA-4 = Very late antigen-4 WM = Waldenstrom macroglobulinemia ACCEPTED MANUSCRIPT 1. Introduction B cell lymphomas encompass a variety of neoplasms affecting lymphocytes in the immune system. In all cases, a normal B cell acquires a set of mutations or genetic aberrations that result in clonal proliferation of malignant cells. The stage of development a B cell is in when it acquires these genetic alterations dictates the subsequent lymphoma that develops. Through advances such as next generation sequencing and high throughput screening technologies, the underlying genetics and mechanisms of lymphomagenesis are becoming more clearly defined. GPCRs are seven-transmembrane domain cell surface-spanning receptors that regulate and transmit extracellular signals to induce numerous intracellular signaling pathways. There are hundreds of known GPCRs, each of which binds a specific ligand or set of ligands, which then induce conformational changes that lead to downstream signaling events. The cell surface ligand-binding capabilities of GPCRs make them highly desirable as drug targets for oncogenic cells. A complete and thorough understanding of GPCR expression in normal and malignant cells, coupled with a detailed knowledge of the molecules that bind to each GPCR and the downstream signaling pathways they activate, will reveal numerous opportunities for targeted therapeutics to improve disease outcome. A summary of what is known regarding GPCR expression and mutation in B cell lymphomas is reviewed here and outlined in Figure 1. 2. B-cell Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia (ALL) is a neoplasm of the lymphoid precursor cells and is characterized as either B cell ALL (B-ALL) or T cell ALL (T-ALL) based on the cell of origin. B-ALL is the most common childhood malignancy and occurs less frequently in adults [1]. B-ALL cases are often subgrouped based on cell of origin, patient age, or the presence of a chromosomal aberration. Multiple chemokine receptors are expressed in B-ALL and these findings are summarized in Table 1. Chemokine receptor expression frequently varies between lineage-derived subgroups of B-ALL and this can provide insight into the underlying function of GPCRs in B-cell development and lymphomagenesis. For example, CXCR1 surface protein was not found in pro-B or pre-B ALL but was present in 5/17 (29%) cases of early pre-B and 3/5 (60%) cases of B-ALL [2]. Meanwhile, flow cytometry of CXCR2 and CXCR3 found these receptors to be expressed in all early pre-B, pre-B and B-ALL samples tested along with more than half of pro-B samples [2, 3]. However, another study that usedACCEPTED immunohistochemistry (IHC MANUSCRIPT) instead of flow cytometry to detect surface protein only found CXCR3 in 3/9 (33%) lymphoblastic leukemia/lymphoma patients [4]. CXCR4 is the most frequently studied chemokine receptor in lymphoma and its role in signaling in B-ALL has been extensively reviewed [5]. CXCR4 is normally expressed on pre-B and mature B cells and is essential for migration in lymphoma [4]. Elevated mRNA or protein expression of CXCR4 in B-ALL has been correlated with unfavorable clinical outcome [6], extramedullary organ invasiveness [7, 8], and time point and site of relapse [9]. CXCR4 has been identified in the majority of pro-B, pre-B and B-ALL cases and in ACCEPTED MANUSCRIPT some early pre-B cases [2, 3, 8, 10]. The estrogen receptor GPER1 (also known as GPR30) is also believed to regulate CXCR4 signaling in pre-B cell ALL [11]. CXCR5 is known to play a role in signaling and cell migration in lymphoma, however there are conflicting reports regarding its cell surface expression in B-ALL. Two flow cytometry studies did not identify any precursor-B, pro-B or pre-B patients with CXCR5 expressed [3, 10] while a third study found CXCR5+ cases in 3/9 (33%) pro-B, 5/17 (29%) early pre-B, 4/12 (33%) pre-B and 5/5 (100%) B-ALL cases [2]. A fourth report identified CXCR5 expression only on CD23+CD5+ B-ALL cells [12], while a final study found the receptor to be expressed in all B-ALL cases [4]. Other chemokine receptors that have been detected by flow cytometry in B-ALL include CCR3 and CCR4 [2, 12] as well as CXCR7 (also known as ACKR3), which is strongly upregulated in the bone marrow in B-ALL compared to normal tissue and plays a role in controlling CXCR4-mediated migration [13]. CCR7 cell surface expression has been found to vary between studies [2, 3, 12] while CCR1, CCR2, CCR5 and CCR6 were extremely rarely or never expressed [2, 3, 10, 14]. In addition to grouping cases of B-ALL by cell of origin, these lymphomas can also be subcharacterized by genetic rearrangements. Fusion of the purinergic receptor P2RY8 promoter to the CRLF2 (cytokine receptor like factor 2) gene frequently occurs in B-ALL but reports of the functional consequences of this rearrangement have been conflicting. Although P2RY8-CRLF2 fusions were significantly correlated with poor outcome in adolescent and adult patients [15, 16], the consequences of the fusion in pediatric B-ALL is less clear as some studies have found it to be associated with poor outcome [17-19] whereas others have not found any significant correlation [20, 21]. A meta-analysis of these studies concluded that presence of the P2RY8-CRLF2 fusion was in fact significantly associated with poor prognosis of relapse-free survival and event-free survival [22]. Another finding among these studies was that P2RY8-CRLF2 was more common in B-ALL patients with trisomy 21 [19, 23-26] or intrachromosomal amplification of chromosome 21 [27] than those with normal chromosome 21 [1, 18-21, 25, 26, 28-30].
Load more

Recommended publications
  • Vasopressin Release from the Rat Hypothalamo-Neurohypophysial System: Effects of Tachykinin NK–1 and NK–2 Receptors Agonis
    Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © 2005 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu Vasopressin release from the rat hypothalamo-neurohy- pophysial system: Effects of tachykinin NK–1 and NK–2 receptors agonists and antagonists ARTICLE ORIGINAL Marlena Juszczak Department of Pathophysiology, Medical University of Lodz, Lodz, Poland. Correspondence to: Marlena Juszczak, Ph.D., D.Sc. Department of Pathophysiology Medical University of Lodz Narutowicza 60 90-136 Lodz, POLAND TEL/FAX: +48 42 6306187 [email protected] Submitted: July 7, 2004 Accepted: October 15, 2004 Key words: tachykinin receptors; substance P; neurokinin A; vasopressin Neuroendocrinol Lett 2005; 26(4):367–372 PMID: 16136007 NEL260405A13 © Neuroendocrinology Letters www.nel.edu Abstract OBJECTIVES: Present experiments were undertaken to study the influence of pep- tide NK–1 and NK–2 receptor agonists and antagonists as well as substance P and neurokinin A (the natural ligands for these tachykinin receptors) on vasopres- sin (AVP) secretion from the rat hypothalamo-neurohypophysial (HN) system in vitro. RESULTS: The results showed that both substance P and highly selective tachykinin 9 11 NK–1 receptor agonist, i.e., [Sar ,Met(O2) ]-Substance P, enhanced significantly AVP secretion, while the NK–1 receptor antagonist (Tyr6,D–Phe7,D–His9)-Sub- stance P (6–11) – sendide – was found to antagonize the substance P–induced hormone release from isolated rat HN system (all peptides at the concentration of 10–7 M/L). The NK–2 receptor selective agonist (β–Ala8)–Neurokinin A (4–10) was essentially inactive in modifying AVP release from the rat HN system in vitro, while neurokinin A (the natural ligand for this tachykinin receptor) was found to stimulate the AVP release; this effect of neurokinin A has been diminished by the 5 6,8,9 10 NK–2 receptor antagonist (Tyr ,D–Trp ,Lys–NH2 )–Neurokinin A (4–10).
    [Show full text]
  • Strategies to Increase ß-Cell Mass Expansion
    This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Strategies to increase -cell mass expansion Drynda, Robert Lech Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 Strategies to increase β-cell mass expansion A thesis submitted by Robert Drynda For the degree of Doctor of Philosophy from King’s College London Diabetes Research Group Division of Diabetes & Nutritional Sciences Faculty of Life Sciences & Medicine King’s College London 2017 Table of contents Table of contents .................................................................................................
    [Show full text]
  • Population-Specific Associations of Deleterious Rare Variants In
    International Journal of Molecular Sciences Article Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients Piotr K. Janicki 1, Ceren Eyileten 2 ID , Victor Ruiz-Velasco 3, Khaled Anwar Sedeek 3, Justyna Pordzik 2, Anna Czlonkowska 2,4, Iwona Kurkowska-Jastrzebska 4 ID , Shigekazu Sugino 1, Yuka Imamura-Kawasawa 5, Dagmara Mirowska-Guzel 2 and Marek Postula 1,2,* ID 1 Perioperative Genomics Laboratory, Penn State College of Medicine, Hershey, PA 17033, USA; [email protected] (P.K.J.); [email protected] (S.S.) 2 Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, 02-097 Warsaw, Poland; [email protected] (C.E.); [email protected] (J.P.); [email protected] (A.C.); [email protected] (D.M.-G.) 3 Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, PA 17033, USA; [email protected] (V.R.-V.); [email protected] (K.A.S.) 4 2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland; [email protected] 5 Genome Sciences Facility, Penn State College of Medicine, Hershey, PA 17033, USA; [email protected] * Correspondence: [email protected]; Tel.: +48-221-166-160 Received: 20 September 2017; Accepted: 7 December 2017; Published: 11 December 2017 Abstract: The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MAF < 1%) to the IS genetic susceptibility in this population.
    [Show full text]
  • The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands
    The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands Clare Louise Wishart Submitted in accordance with the requirements for the degree of Doctor of Philosophy of Science University of Leeds School of Biomedical Sciences Faculty of Biological Sciences September 2013 I Intellectual Property and Publication Statements The candidate confirms that the work submitted is her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Clare Louise Wishart to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. © 2013 The University of Leeds and Clare Louise Wishart. II Acknowledgments Firstly I would like to offer my sincerest thanks and gratitude to my supervisor, Dr. Dan Donnelly, who has been nothing but encouraging and engaging from day one. I have thoroughly enjoyed every moment of working alongside him and learning from his guidance and wisdom. My thanks go to my academic assessor Professor Paul Milner whom I have known for several years, and during my time at the University of Leeds he has offered me invaluable advice and inspiration. Additionally I would like to thank my academic project advisor Dr. Michael Harrison for his friendship, help and advice. I would like to thank Dr. Rosalind Mann and Dr. Elsayed Nasr for welcoming me into the lab as a new PhD student and sharing their experimental techniques with me, these techniques have helped me no end in my time as a research student.
    [Show full text]
  • F2RL2 Antibody Cat
    F2RL2 Antibody Cat. No.: 56-323 F2RL2 Antibody F2RL2 Antibody immunohistochemistry analysis in formalin fixed and paraffin embedded human heart tissue followed by peroxidase conjugation of the secondary antibody and DAB staining. Specifications HOST SPECIES: Rabbit SPECIES REACTIVITY: Human This F2RL2 antibody is generated from rabbits immunized with a KLH conjugated IMMUNOGEN: synthetic peptide between 21-50 amino acids from the N-terminal region of human F2RL2. TESTED APPLICATIONS: IHC-P, WB For WB starting dilution is: 1:1000 APPLICATIONS: For IHC-P starting dilution is: 1:10~50 PREDICTED MOLECULAR 43 kDa WEIGHT: September 25, 2021 1 https://www.prosci-inc.com/f2rl2-antibody-56-323.html Properties This antibody is purified through a protein A column, followed by peptide affinity PURIFICATION: purification. CLONALITY: Polyclonal ISOTYPE: Rabbit Ig CONJUGATE: Unconjugated PHYSICAL STATE: Liquid BUFFER: Supplied in PBS with 0.09% (W/V) sodium azide. CONCENTRATION: batch dependent Store at 4˚C for three months and -20˚C, stable for up to one year. As with all antibodies STORAGE CONDITIONS: care should be taken to avoid repeated freeze thaw cycles. Antibodies should not be exposed to prolonged high temperatures. Additional Info OFFICIAL SYMBOL: F2RL2 Proteinase-activated receptor 3, PAR-3, Coagulation factor II receptor-like 2, Thrombin ALTERNATE NAMES: receptor-like 2, F2RL2, PAR3 ACCESSION NO.: O00254 GENE ID: 2151 USER NOTE: Optimal dilutions for each application to be determined by the researcher. Background and References Coagulation factor II (thrombin) receptor-like 2 (F2RL2) is a member of the large family of 7-transmembrane-region receptors that couple to guanosine-nucleotide-binding proteins.
    [Show full text]
  • Substance P Antagonists As a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury
    Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Substance P Antagonists as a Therapeutic Approach to Improving Outcome Following Traumatic Brain Injury Robert Vink and Corinna van den Heuvel School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia, 5005 Summary: Although a number of secondary injury factors are been implicated in learning and memory, mood and anxiety, known to contribute to the development of morphological in- stress mechanisms, emotion-processing, migraine, emesis, jury and functional deficits following traumatic brain injury, pain, and seizures, all of which may be adversely affected accumulating evidence has suggested that neuropeptides, after brain injury. Inhibition of post-traumatic substance P and in particular substance P, may play a critical role. Sub- activity, either by preventing release or by antagonism of the stance P is released early following acute injury to the CNS neurokinin-1 receptor, has consistently resulted in a pro- as part of a neurogenic inflammatory response. In so doing, found decrease in development of edema and marked im- it facilitates an increase in the permeability of the blood– provements in functional outcome. This review summarizes brain barrier and the development of vasogenic edema. At the current evidence supporting a role for substance P in the cellular level, substance P has been shown to directly acute brain injury. Key Words: Neurotrauma, inflammation, result in neuronal cell death; functionally, substance P has edema, substance P, tachykinins. INTRODUCTION to prevent further injury and improve outcome. Accord- ingly, a significant research effort has been directed at Traumatic brain injury (TBI) is the leading cause of identifying secondary injury factors and then developing death and disability in people under 40 years of age in novel therapies that may attenuate, or even prevent, their developed countries.1 Although the costs for treatment, action.
    [Show full text]
  • P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases
    International Journal of Molecular Sciences Review P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases Derek Strassheim 1, Alexander Verin 2, Robert Batori 2 , Hala Nijmeh 3, Nana Burns 1, Anita Kovacs-Kasa 2, Nagavedi S. Umapathy 4, Janavi Kotamarthi 5, Yash S. Gokhale 5, Vijaya Karoor 1, Kurt R. Stenmark 1,3 and Evgenia Gerasimovskaya 1,3,* 1 The Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] (D.S.); [email protected] (N.B.); [email protected] (V.K.); [email protected] (K.R.S.) 2 Vascular Biology Center, Augusta University, Augusta, GA 30912, USA; [email protected] (A.V.); [email protected] (R.B.); [email protected] (A.K.-K.) 3 The Department of Pediatrics, Division of Critical Care Medicine, University of Colorado Denver, Aurora, CO 80045, USA; [email protected] 4 Center for Blood Disorders, Augusta University, Augusta, GA 30912, USA; [email protected] 5 The Department of BioMedical Engineering, University of Wisconsin, Madison, WI 53706, USA; [email protected] (J.K.); [email protected] (Y.S.G.) * Correspondence: [email protected]; Tel.: +1-303-724-5614 Received: 25 August 2020; Accepted: 15 September 2020; Published: 18 September 2020 Abstract: Purinergic G-protein-coupled receptors are ancient and the most abundant group of G-protein-coupled receptors (GPCRs). The wide distribution of purinergic receptors in the cardiovascular system, together with the expression of multiple receptor subtypes in endothelial cells (ECs) and other vascular cells demonstrates the physiological importance of the purinergic signaling system in the regulation of the cardiovascular system.
    [Show full text]
  • The Role of Platelet Thrombin Receptors PAR1 and PAR4 in Health and Disease
    Linköping University Medical Dissertations No 1261 The role of platelet thrombin receptors PAR1 and PAR4 in health and disease Martina Nylander Division of Clinical Chemistry Department of Clinical and Experimental Medicine Linköping University, Sweden Linköping 2011 © Martina Nylander, 2011 Published papers are reprinted with the permission from the copyright holder. The role of platelet thrombin receptors PAR1 and PAR4 in health and disease Cover: A drawing made by the author, illustrating PAR1 & PAR4 cell signaling. Printed in Sweden by LiU-tryck, Linköping, Sweden, 2011 ISBN: 978-91-7393-067-3 ISSN: 0345-0082 ”Life is a mystery” -Julien Offray de La Mettrie To all my dear friends standing steady on earth or flying in the sky ABSTRACT Blood cells are continuously flowing in our systems maintaining haemostasis in the arteries and veins. If a vessel is damaged, the smallest cell fragments in the blood (platelets) are directed to cover the wound and plug the leakage to prevent blood loss. Most of the time platelets stop the blood leak without any difficulties. During other, pathological, circumstances, platelets continue to form a thrombus, preventing the blood flow and may cause myocardial infarction or stroke. Thrombin is the most potent platelet agonist and is a product created in the coagulation cascade. This thesis is focused on the interactions between the two platelet thrombin receptors; protease activated receptors 1 (PAR1) and PAR4 in vitro. We have investigated potential differences between these receptors in several situations associated with cardiovascular disease. First we studied interactions between PAR1 and PAR4 and the oral pathogen Porphyromonas gingivalis (which secretes enzymes, gingipains, with properties similar to thrombin).
    [Show full text]
  • Effect of Prostanoids on Human Platelet Function: an Overview
    International Journal of Molecular Sciences Review Effect of Prostanoids on Human Platelet Function: An Overview Steffen Braune, Jan-Heiner Küpper and Friedrich Jung * Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology, 01968 Senftenberg, Germany; steff[email protected] (S.B.); [email protected] (J.-H.K.) * Correspondence: [email protected] Received: 23 October 2020; Accepted: 23 November 2020; Published: 27 November 2020 Abstract: Prostanoids are bioactive lipid mediators and take part in many physiological and pathophysiological processes in practically every organ, tissue and cell, including the vascular, renal, gastrointestinal and reproductive systems. In this review, we focus on their influence on platelets, which are key elements in thrombosis and hemostasis. The function of platelets is influenced by mediators in the blood and the vascular wall. Activated platelets aggregate and release bioactive substances, thereby activating further neighbored platelets, which finally can lead to the formation of thrombi. Prostanoids regulate the function of blood platelets by both activating or inhibiting and so are involved in hemostasis. Each prostanoid has a unique activity profile and, thus, a specific profile of action. This article reviews the effects of the following prostanoids: prostaglandin-D2 (PGD2), prostaglandin-E1, -E2 and E3 (PGE1, PGE2, PGE3), prostaglandin F2α (PGF2α), prostacyclin (PGI2) and thromboxane-A2 (TXA2) on platelet activation and aggregation via their respective receptors. Keywords: prostacyclin; thromboxane; prostaglandin; platelets 1. Introduction Hemostasis is a complex process that requires the interplay of multiple physiological pathways. Cellular and molecular mechanisms interact to stop bleedings of injured blood vessels or to seal denuded sub-endothelium with localized clot formation (Figure1).
    [Show full text]
  • Regulation of Immune Cells by Eicosanoid Receptors
    Regulation of Immune Cells by Eicosanoid Receptors The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Kim, Nancy D., and Andrew D. Luster. 2007. “Regulation of Immune Cells by Eicosanoid Receptors.” The Scientific World Journal 7 (1): 1307-1328. doi:10.1100/tsw.2007.181. http://dx.doi.org/10.1100/ tsw.2007.181. Published Version doi:10.1100/tsw.2007.181 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37298366 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Review Article Special Issue: Eicosanoid Receptors and Inflammation TheScientificWorldJOURNAL (2007) 7, 1307–1328 ISSN 1537-744X; DOI 10.1100/tsw.2007.181 Regulation of Immune Cells by Eicosanoid Receptors Nancy D. Kim and Andrew D. Luster* Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston E-mail: [email protected] Received March 13, 2007; Revised June 14, 2007; Accepted July 2, 2007; Published September 1, 2007 Eicosanoids are potent, bioactive, lipid mediators that regulate important components of the immune response, including defense against infection, ischemia, and injury, as well as instigating and perpetuating autoimmune and inflammatory conditions. Although these lipids have numerous effects on diverse cell types and organs, a greater understanding of their specific effects on key players of the immune system has been gained in recent years through the characterization of individual eicosanoid receptors, the identification and development of specific receptor agonists and inhibitors, and the generation of mice genetically deficient in various eicosanoid receptors.
    [Show full text]
  • Activation of the Murine EP3 Receptor for PGE2 Inhibits Camp Production and Promotes Platelet Aggregation
    Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation Jean-Etienne Fabre, … , Thomas M. Coffman, Beverly H. Koller J Clin Invest. 2001;107(5):603-610. https://doi.org/10.1172/JCI10881. Article The importance of arachidonic acid metabolites (termed eicosanoids), particularly those derived from the COX-1 and COX-2 pathways (termed prostanoids), in platelet homeostasis has long been recognized. Thromboxane is a potent agonist, whereas prostacyclin is an inhibitor of platelet aggregation. In contrast, the effect of prostaglandin E2 (PGE2) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE2 enhance platelet aggregation, whereas high PGE2 levels inhibit aggregation. The mechanism for this dual action of PGE2 is not clear. This study shows that among the four PGE2 receptors (EP1–EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE2 concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE2 concentrations. Furthermore, the relative activation of these two receptors, EP3 and IP, regulates the intracellular level of cAMP and in this way conditions the response of the platelet to aggregating agents. Consistent with these findings, loss of the EP3 receptor in a model of venous inflammation protects against formation of intravascular clots. Our results suggest that local production of PGE2 during an inflammatory process can modulate ensuing platelet responses. Find the latest version: https://jci.me/10881/pdf Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation Jean-Etienne Fabre,1 MyTrang Nguyen,1 Krairek Athirakul,2 Kenneth Coggins,1 John D.
    [Show full text]
  • Multi-Functionality of Proteins Involved in GPCR and G Protein Signaling: Making Sense of Structure–Function Continuum with In
    Cellular and Molecular Life Sciences (2019) 76:4461–4492 https://doi.org/10.1007/s00018-019-03276-1 Cellular andMolecular Life Sciences REVIEW Multi‑functionality of proteins involved in GPCR and G protein signaling: making sense of structure–function continuum with intrinsic disorder‑based proteoforms Alexander V. Fonin1 · April L. Darling2 · Irina M. Kuznetsova1 · Konstantin K. Turoverov1,3 · Vladimir N. Uversky2,4 Received: 5 August 2019 / Revised: 5 August 2019 / Accepted: 12 August 2019 / Published online: 19 August 2019 © Springer Nature Switzerland AG 2019 Abstract GPCR–G protein signaling system recognizes a multitude of extracellular ligands and triggers a variety of intracellular signal- ing cascades in response. In humans, this system includes more than 800 various GPCRs and a large set of heterotrimeric G proteins. Complexity of this system goes far beyond a multitude of pair-wise ligand–GPCR and GPCR–G protein interactions. In fact, one GPCR can recognize more than one extracellular signal and interact with more than one G protein. Furthermore, one ligand can activate more than one GPCR, and multiple GPCRs can couple to the same G protein. This defnes an intricate multifunctionality of this important signaling system. Here, we show that the multifunctionality of GPCR–G protein system represents an illustrative example of the protein structure–function continuum, where structures of the involved proteins represent a complex mosaic of diferently folded regions (foldons, non-foldons, unfoldons, semi-foldons, and inducible foldons). The functionality of resulting highly dynamic conformational ensembles is fne-tuned by various post-translational modifcations and alternative splicing, and such ensembles can undergo dramatic changes at interaction with their specifc partners.
    [Show full text]