DOCSLIB.ORG

Receptor Structure-Based Discovery of Non-Metabolite Agonists for the Succinate Receptor GPR91

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Receptor Structure-Based Discovery of Non-Metabolite Agonists for the Succinate Receptor GPR91 Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91 Trauelsen, Mette; Rexen Ulven, Elisabeth; Hjorth, Siv A; Brvar, Matjaz; Monaco, Claudia; Frimurer, Thomas M; Schwartz, Thue W Published in: Molecular Metabolism DOI: 10.1016/j.molmet.2017.09.005 Publication date: 2017 Document version Publisher's PDF, also known as Version of record Document license: CC BY-NC-ND Citation for published version (APA): Trauelsen, M., Rexen Ulven, E., Hjorth, S. A., Brvar, M., Monaco, C., Frimurer, T. M., & Schwartz, T. W. (2017). Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91. Molecular Metabolism, 6(12), 1585-1596. https://doi.org/10.1016/j.molmet.2017.09.005 Download date: 08. apr.. 2020 Original Article Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91 Mette Trauelsen 1, Elisabeth Rexen Ulven 3, Siv A. Hjorth 2, Matjaz Brvar 3, Claudia Monaco 4, Thomas M. Frimurer 1,*, Thue W. Schwartz 1,2,* ABSTRACT Objective: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools. Methods and results: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a substructure-based search query, which, combined with molecular docking, was used in virtual screening of the ZINC database to pick two serial mini-libraries of a total of only 245 compounds from which sub-micromolar, selective GPR91 agonists of unique structures were identified. The best compounds were backbone-modified succinate analogs in which an amide-linked hydrophobic moiety docked into the side-pocket next to succinate as shown by both loss- and gain-of-function mutagenesis. These compounds displayed GPR91-dependent activity in altering cytokine expression in human M2 macrophages similar to succinate, and importantly were devoid of any effect on the major intracellular target, succinate dehydrogenase. Conclusions: These novel, synthetic non-metabolite GPR91 agonists will be valuable both as pharmacological tools to delineate the GPR91- mediated functions of succinate and as leads for the development of GPR91-targeted drugs to potentially treat low grade metabolic inflam- mation and diabetic complications such as retinopathy and nephropathy. Ó 2017 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords GPR91; SUCNR1; Metabolite receptor; GPCR; Drug discovery; Virtual screening; Chemical design 1. INTRODUCTION During normal physiological conditions, plasma levels of succinate range between 2 and 30 mM for humans and 6e17 mM for rodents It is becoming increasingly clear that key metabolites function not only as [5e8]. These levels are below the reported EC50 values for GPR91 energy sources and building blocks but can act also as extracellular activation [1]; however, metabolic stress conditions such as hyper- messengers signaling through G protein coupled receptors (GPCRs) glycemia and hypoxia cause the levels of succinate to rise both locally similarly to hormones and neurotransmitters [1].Succinate,whichhas and in the circulation, enabling activation of GPR91 [5,7,9e11]. for many years solely has been viewed as a TCA cycle intermediate, is Notably, several of the classical rodent models of metabolic dysfunc- one of these signaling metabolites. Already in 2004, succinate was tion have all displayed elevated plasma levels of succinate [7],afinding shown to be the ligand for the G-protein coupled receptor (GPCR) GPR91 also established in patients suffering from Type 2 diabetes (T2D) [12]. [2]. The receptor was predominantly found to be expressed in the kidney, GPR91 has been proposed to be involved in the development of dia- spleen, liver, and small intestine [2]. In the following years most attention betes complications including neuronal VEGF-mediated neo- was paid to the pro-hypertensive effect of GPR91 associated with renin- vascularization in diabetic retinopathy [3,13,14] as well as in diabetic release [3]. In the liver, stress-induced succinate accumulation and nephropathy [9,15]. Adipocytes also express GPR91 and activation of GPR91 activation has been linked to development of fibrosis due to its the receptor inhibits lipolysis [16]. The physiological role of GPR91 on expression in hepatic stellate cells, which, upon succinate stimulation, whole body metabolism, however, is still unclear as GPR91 deficiency produces fibrogenic factors in a GPR91-dependent manner [4,5]. in mice challenged with HFD has been reported both to give impaired 1NNF Center for Basic Metabolic Research, Section for Metabolic Receptology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark 2Laboratory for Molecular Pharmacology, Department of Biomedical Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark 3Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark 4Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, OX3 7FY Oxford, UK *Corresponding authors. Novo Nordisk Foundation Center For Basic Metabolic Research, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark. E-mails: thomas.frimurer@sund. ku.dk (T.M. Frimurer), [email protected] (T.W. Schwartz). Received August 23, 2017 Revision received September 14, 2017 Accepted September 25, 2017 Available online 30 September 2017 https://doi.org/10.1016/j.molmet.2017.09.005 MOLECULAR METABOLISM 6 (2017) 1585e1596 Ó 2017 The Authors. Published by ElsevierGmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1585 www.molecularmetabolism.com Original Article [17] and improved glucose tolerance [12]. McCreath and colleagues and Key Organics. Succinate and other small carboxylic acids for Ò also observed dramatic changes in WAT composition [17], something Figure 1 were purchased from SigmaeAldrich and Akos. that also was not confirmed by van Diepen et al., who notably proposed All purchased compounds were spun down and subsequently dissolved that a dramatic decrease in infiltrating macrophages was the main in 100% dimethyl sulfoxide (DMSO) to achieve a final concentration of driver of the improved glucose tolerance in GPR91 deficient mice [12]. 50 mM and left to shake overnight. Dilution rows of the 50 mM stock In fact, GPR91 does seem to be an important regulator of innate im- solutions were subsequently prepared to obtain concentrations suitable munity, particularly as an activator of dendritic cells [18] and macro- for cell-based assays. It is important to mention that all presented phages [19]. structures were confirmed using proton (1H) NMR spectra at 300/ Importantly, independent of GPR91 signaling, succinate can cause a 400 MHz and liquid chromatographyÀmass spectrometry (LC-MS) number of intracellular responses, including post translational modi- analysis confirmed a minimum purity of 95% for all compounds. fications [20], HIF-1a stabilization [21], production of mitochondrial reactive oxygen species (ROS) [11], and overall changes to cellular 2.2. Synthesis of enantiomerically pure compounds metabolism owing to its central role in the TCA cycle. Due to such non- All enantiomerically pure compounds were synthesized by the same receptor mediated effects, the endogenous metabolite succinate as general route. D-orL-aspartate protected as the corresponding such is not a reliable agent to delineate the specific physiological dimethyl esters were coupled with the appropriate carboxylic acid importance of GPR91. The aim of the present study, therefore, was to building block using fluoro-N, N, N0, N0-bis(tetramethylene)for- develop drug-like non-metabolite GPR91 agonists as potential phar- mamidinium hexafluorophosphate [22]. Lithium hydroxide-promoted macological tools by use of a receptor structure-based approach. ester hydrolysis gave the desired test compounds. The acid building blocks were either commercially available (compound 184), or syn- 2. MATERIALS AND METHODS thesized by Williamson ether synthesis (compound 131) or by Suzuki cross coupling using Buchwald’s fourth generation XPhos precatalyst 2.1. Compound acquisition and preparation [23] (compound 130), both followed by ester hydrolysis. Detailed Ligands for library 1 and 2 were purchased from a range of vendors procedures and compound characterization can be found in the including Enamines, Vitas-M Laboratories, ChemDIv, Interbioscreen, Supplementary information. Figure 1: GPR91 activation properties of TCA cycle metabolites and synthetic succinate analogs. A) The main metabolites of the TCA cycle are depicted with structures. Compounds that are able to activate GPR91 are indicated in green and inactive compounds are in gray. B) Dose response curves for the ‘active’ succinate analogs measured
Load more

Recommended publications
  • Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-Helminth Immunity in the Small Intestine but Are Dispensable for Anti-Protist Immunity
    Article Tuft-Cell-Derived Leukotrienes Drive Rapid Anti- helminth Immunity in the Small Intestine but Are Dispensable for Anti-protist Immunity Graphical Abstract Authors John W. McGinty, Hung-An Ting, Tyler E. Billipp, ..., Hong-Erh Liang, Ichiro Matsumoto, Jakob von Moltke Correspondence [email protected] In Brief Tuft cells regulate type 2 immunity in the small intestine by secreting the cytokine IL-25. McGinty et al. identify cysteinyl leukotriene production as an additional tuft cell effector function. Tuft-cell- derived leukotrienes drive anti-helminth immunity in the intestine but are dispensable for the response induced by tritrichomonad protists. Highlights d Cysteinyl leukotrienes activate intestinal ILC2s d Cysteinyl leukotrienes drive rapid anti-helminth type 2 immune responses d Tuft cells are the source of cysteinyl leukotrienes during helminth infection d Tuft-cell-derived leukotrienes are not required for the anti- protist response McGinty et al., 2020, Immunity 52, 528–541 March 17, 2020 ª 2020 Elsevier Inc. https://doi.org/10.1016/j.immuni.2020.02.005 Immunity Article Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-helminth Immunity in the Small Intestine but Are Dispensable for Anti-protist Immunity John W. McGinty,1 Hung-An Ting,1 Tyler E. Billipp,1 Marija S. Nadjsombati,1 Danish M. Khan,1 Nora A. Barrett,2 Hong-Erh Liang,3,4 Ichiro Matsumoto,5 and Jakob von Moltke1,6,* 1Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA 2Division of Rheumatology, Immunology and Allergy, Jeff
    [Show full text]
  • Viewed Under 23 (B) Or 203 (C) fi M M Male Cko Mice, and Largely Unaffected Magni Cation; Scale Bars, 500 M (B) and 50 M (C)
    BRIEF COMMUNICATION www.jasn.org Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron Camille Ansermet,* Matthias B. Moor,* Gabriel Centeno,* Muriel Auberson,* † † ‡ Dorothy Zhang Hu, Roland Baron, Svetlana Nikolaeva,* Barbara Haenzi,* | Natalya Katanaeva,* Ivan Gautschi,* Vladimir Katanaev,*§ Samuel Rotman, Robert Koesters,¶ †† Laurent Schild,* Sylvain Pradervand,** Olivier Bonny,* and Dmitri Firsov* BRIEF COMMUNICATION *Department of Pharmacology and Toxicology and **Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland; †Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts; ‡Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia; §School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; |Services of Pathology and ††Nephrology, Department of Medicine, University Hospital of Lausanne, Lausanne, Switzerland; and ¶Université Pierre et Marie Curie, Paris, France ABSTRACT Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is crit- leaves.4 Most recently, Legati et al. have ical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the shown an association between genetic kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical polymorphisms in Xpr1 and primary fa- sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the milial brain calcification disorder.5 How- molecular identity of the protein(s) participating in the basolateral Pi efflux remains ever, the role of XPR1 in the maintenance unknown. Evidence has suggested that xenotropic and polytropic retroviral recep- of Pi homeostasis remains unknown. Here, tor 1 (XPR1) might be involved in this process. Here, we show that conditional in- we addressed this issue in mice deficient for activation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi Xpr1 in the nephron.
    [Show full text]
  • Edinburgh Research Explorer
    Edinburgh Research Explorer International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list Citation for published version: Davenport, AP, Alexander, SPH, Sharman, JL, Pawson, AJ, Benson, HE, Monaghan, AE, Liew, WC, Mpamhanga, CP, Bonner, TI, Neubig, RR, Pin, JP, Spedding, M & Harmar, AJ 2013, 'International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands', Pharmacological reviews, vol. 65, no. 3, pp. 967-86. https://doi.org/10.1124/pr.112.007179 Digital Object Identifier (DOI): 10.1124/pr.112.007179 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Pharmacological reviews Publisher Rights Statement: U.S. Government work not protected by U.S. copyright General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file 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 1521-0081/65/3/967–986$25.00 http://dx.doi.org/10.1124/pr.112.007179 PHARMACOLOGICAL REVIEWS Pharmacol Rev 65:967–986, July 2013 U.S.
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]
  • G Protein‐Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: G protein-coupled receptors. British Journal of Pharmacology (2019) 176, S21–S141 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors Stephen PH Alexander1 , Arthur Christopoulos2 , Anthony P Davenport3 , Eamonn Kelly4, Alistair Mathie5 , John A Peters6 , Emma L Veale5 ,JaneFArmstrong7 , Elena Faccenda7 ,SimonDHarding7 ,AdamJPawson7 , Joanna L Sharman7 , Christopher Southan7 , Jamie A Davies7 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia 3Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK 4School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 5Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 6Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 7Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website.
    [Show full text]
  • Cell Differentiation Is Disrupted by MYO5B Loss Through Wnt/Notch Imbalance
    Cell differentiation is disrupted by MYO5B loss through Wnt/Notch imbalance Izumi Kaji, … , Masahiko Watanabe, James R. Goldenring JCI Insight. 2021;6(16):e150416. https://doi.org/10.1172/jci.insight.150416. Research Article Gastroenterology Functional loss of myosin Vb (MYO5B) induces a variety of deficits in intestinal epithelial cell function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). The impact of MYO5B loss on differentiated cell lineage choice has not been investigated. We quantified the populations of differentiated epithelial cells in tamoxifen- induced, epithelial cell–specific MYO5B-knockout (VilCreERT2 Myo5bfl/fl) mice utilizing digital image analysis. Consistent with our RNA-sequencing data, MYO5B loss induced a reduction in tuft cells in vivo and in organoid cultures. Paneth cells were significantly increased by MYO5B deficiency along with expansion of the progenitor cell zone. We further investigated the effect of lysophosphatidic acid (LPA) signaling on epithelial cell differentiation. Intraperitoneal LPA significantly increased tuft cell populations in both control and MYO5B-knockout mice. Transcripts for Wnt ligands were significantly downregulated by MYO5B loss in intestinal epithelial cells, whereas Notch signaling molecules were unchanged. Additionally, treatment with the Notch inhibitor dibenzazepine (DBZ) restored the populations of secretory cells, suggesting that the Notch pathway is maintained in MYO5B-deficient intestine. MYO5B loss likely impairs progenitor cell differentiation in the small intestine in vivo and in vitro, partially mediated by Wnt/Notch imbalance. Notch inhibition and/or LPA treatment may represent an effective therapeutic approach for treatment of MVID. Find the latest version: https://jci.me/150416/pdf RESEARCH ARTICLE Cell differentiation is disrupted by MYO5B loss through Wnt/Notch imbalance Izumi Kaji,1,2 Joseph T.
    [Show full text]
  • Succinate Receptors in the Kidney
    BRIEF REVIEW www.jasn.org Succinate Receptors in the Kidney Peter M.T. Deen and Joris H. Robben Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands ABSTRACT The G protein–coupled succinate and ␣-ketoglutarate receptors are closely related to nyl-CoA synthetase and subsequently the family of P2Y purinoreceptors. Although the ␣-ketoglutarate receptor is almost converted by succinate dehydrogenase exclusively expressed in the kidney, its function is unknown. In contrast, the succinate to generate fumarate. Because the suc- receptor, SUCRN1, is expressed in a variety of tissues, including blood cells, adipose cinate dehydrogenase complex is part of the tissue, liver, retina, and the kidney. Recent evidence suggests SUCRN1 and its succi- electron transport chain in the mitochon- nate ligand are novel detectors of local stress, including ischemia, hypoxia, toxicity, drial membrane (complex II; Figure 2), its and hyperglycemia. Local levels of succinate in the kidney also activate the renin- activity indirectly depends on the avail- angiotensin system and together with SUCRN1 may play a key role in the develop- ability of oxygen. As such, in situations ment of hypertension and the complications of diabetes mellitus, metabolic disease, when oxygen tension is low, succinate and liver damage. This makes the succinate receptor a promising drug target to accumulates because of low activity of counteract an expanding number of interrelated disorders. succinate dehydrogenase or other en- zymes in the electron transport chain J Am Soc Nephrol 22: 1416–1422, 2011. doi: 10.1681/ASN.2010050481 that affect its activity.5–7 Low oxygen states, such as ischemia8 or exercise9 also increase circulating levels of succinate.
    [Show full text]
  • Downloaded on 27 May 2020
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.07.438755; this version posted April 7, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Title: Cells of the human intestinal tract mapped across space and time Elmentaite R1, Kumasaka N1, King HW2, Roberts K1, Dabrowska M1, Pritchard S1, Bolt L1, Vieira SF1, Mamanova L1, Huang N1, Goh Kai’En I3, Stephenson E3, Engelbert J3, Botting RA3, Fleming A1,4, Dann E1, Lisgo SN3, Katan M7, Leonard S1, Oliver TRW1,8, Hook CE8, Nayak K10, Perrone F10, Campos LS1, Dominguez-Conde C1, Polanski K1, Van Dongen S1, Patel M1, Morgan MD5,6, Marioni JC1,5,6, Bayraktar OA1, Meyer KB1, Zilbauer M9,10,11, Uhlig H12,13,14, Clatworthy MR1,4, Mahbubani KT15, Saeb Parsy K15, Haniffa M1,3, James KR1* & Teichmann SA1,16* Affiliations: 1. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. 2. Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK 3. Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. 4. Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK 5. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK. 6. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK 7. Structural and Molecular Biology, Division of Biosciences, University College London WC1E 6BT, UK 8.
    [Show full text]
  • Activation of Intestinal Tuft Cell-Expressed Sucnr1 Triggers Type 2 Immunity in the Mouse Small Intestine
    Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine Weiwei Leia,1, Wenwen Rena,1, Makoto Ohmotoa, Joseph F. Urban Jr.b, Ichiro Matsumotoa, Robert F. Margolskeea, and Peihua Jianga,2 aMonell Chemical Senses Center, Philadelphia, PA 19104; and bDiet, Genomics and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD 20705 Edited by Robert J. Lefkowitz, Howard Hughes Medical Institute and Duke University Medical Center, Durham, NC, and approved April 19, 2018 (received for review November 28, 2017) The hallmark features of type 2 mucosal immunity include in- Expulsion of the intestinal worm parasite Nippostrongylus brasi- − − testinal tuft and goblet cell expansion initiated by tuft cell liensis from the gut is significantly delayed in Pou2f3 / mice activation. How infectious agents that induce type 2 mucosal compared with wild-type mice (8). The current model suggests tuft immunity are detected by tuft cells is unknown. Published micro- cells detect parasitic infection via taste-signaling elements and se- array analysis suggested that succinate receptor 1 (Sucnr1) is spe- crete the proinflammatory cytokine IL-25, which subsequently cifically expressed in tuft cells. Thus, we hypothesized that the triggers mucosal type 2 responses via IL-13–producing ILC2s and succinate–Sucnr1 axis may be utilized by tuft cells to detect certain IL-13 receptor alpha-expressing intestinal epithelial progenitor cells
    [Show full text]
  • Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Amy Sue Bogard University of Tennessee Health Science Center
    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2013 Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Amy Sue Bogard University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Medical Cell Biology Commons, and the Medical Molecular Biology Commons Recommended Citation Bogard, Amy Sue , "Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells" (2013). Theses and Dissertations (ETD). Paper 330. http://dx.doi.org/10.21007/etd.cghs.2013.0029. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Biomedical Sciences Track Molecular Therapeutics and Cell Signaling Research Advisor Rennolds Ostrom, Ph.D. Committee Elizabeth Fitzpatrick, Ph.D. Edwards Park, Ph.D. Steven Tavalin, Ph.D. Christopher Waters, Ph.D. DOI 10.21007/etd.cghs.2013.0029 Comments Six month embargo expired June 2014 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/330 Adenylyl Cyclase 2 Selectively Regulates IL-6 Expression in Human Bronchial Smooth Muscle Cells A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Amy Sue Bogard December 2013 Copyright © 2013 by Amy Sue Bogard.
    [Show full text]
  • Granzyme a in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging
    Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging This information is current as Robert A. Campbell, Zechariah Franks, Anish Bhatnagar, of September 25, 2021. Jesse W. Rowley, Bhanu K. Manne, Mark A. Supiano, Hansjorg Schwertz, Andrew S. Weyrich and Matthew T. Rondina J Immunol 2018; 200:295-304; Prepublished online 22 November 2017; Downloaded from doi: 10.4049/jimmunol.1700885 http://www.jimmunol.org/content/200/1/295 Supplementary http://www.jimmunol.org/content/suppl/2017/11/22/jimmunol.170088 http://www.jimmunol.org/ Material 5.DCSupplemental References This article cites 47 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/200/1/295.full#ref-list-1 Why The JI? Submit online. by guest on September 25, 2021 • 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 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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Granzyme A in Human Platelets Regulates the Synthesis of Proinflammatory Cytokines by Monocytes in Aging Robert A.
    [Show full text]
  • Target Identification and Probe Development for Pancreatic Neuroendocrine Tumors
    TARGET IDENTIFICATION AND PROBE DEVELOPMENT FOR PANCREATIC NEUROENDOCRINE TUMORS Identifizierung von Zielstrukturen und Sondenentwicklung für pankreatische neuroendokrine Tumore Von der Fakultät Energie‐, Verfahrens‐ und Biotechnik der Universität Stuttgart zur Erlangung der Würde eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigte Abhandlung vorgelegt von Jan Lennart Körner aus Warstein Hauptberichter: Prof. Dr. Roland Kontermann Nebenberichter: Prof. Dr. Christina Wege Tag der mündlichen Prüfung: 19.02.2015 Institut für Zellbiologie und Immunologie Universität Stuttgart 2015 1 INDEX II Table of Contents 1. Glossary .............................................................................................................................. V 2. Abstract ............................................................................................................................ VII 2.1. Zusammenfassung ................................................................................................................ VIII 3. Introduction ........................................................................................................................ 1 3.1. Rationale .................................................................................................................................. 1 3.2. G Protein‐Coupled Receptors .................................................................................................. 1 3.3. GPCR Signal Transduction .......................................................................................................
    [Show full text]