A Unique Signal Sequence of the Chemokine Receptor CCR7 Promotes Package Into COPII Vesicles for Efficient Receptor Trafficking
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Endothelin System and Therapeutic Application of Endothelin Receptor
xperim ACCESS Freely available online & E en OPEN l ta a l ic P in h l a C r m f o a c l a o n l o r g u y o J Journal of ISSN: 2161-1459 Clinical & Experimental Pharmacology Research Article Endothelin System and Therapeutic Application of Endothelin Receptor Antagonists Abebe Basazn Mekuria, Zemene Demelash Kifle*, Mohammedbrhan Abdelwuhab Department of Pharmacology, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia ABSTRACT Endothelin is a 21 amino acid molecule endogenous potent vasoconstrictor peptide. Endothelin is synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonic, and inflammatory cells. It acts through a seven transmembrane endothelin receptor A (ETA) and endothelin receptor B (ETB) receptors belongs to G protein-coupled rhodopsin-type receptor superfamily. This peptide involved in pathogenesis of cardiovascular disorder like (heart failure, arterial hypertension, myocardial infraction and atherosclerosis), renal failure, pulmonary arterial hypertension and it also involved in pathogenesis of cancer. Potentially endothelin receptor antagonist helps the treatment of the above disorder. Currently, there are a lot of trails both per-clinical and clinical on endothelin antagonist for various cardiovascular, pulmonary and cancer disorder. Some are approved by FAD for the treatment. These agents are including both selective and non-selective endothelin receptor antagonist (ETA/B). Currently, Bosentan, Ambrisentan, and Macitentan approved -
Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung’S Disease
RESEARCH ARTICLE Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung’s Disease Ankush Gosain1,2*, Amanda J. Barlow-Anacker1, Chris S. Erickson1, Joseph F. Pierre1, Aaron F. Heneghan1, Miles L. Epstein2, Kenneth A. Kudsk1,3 a11111 1 Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America, 2 Department of Neuroscience, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America, 3 Veteran Administration Surgical Service, William S. Middleton Memorial Veterans Hospital, Madison, United States of America * [email protected] OPEN ACCESS Citation: Gosain A, Barlow-Anacker AJ, Erickson Abstract CS, Pierre JF, Heneghan AF, Epstein ML, et al. (2015) Impaired Cellular Immunity in the Murine Hirschsprung’s disease (HSCR) is characterized by aganglionosis from failure of neural crest Neural Crest Conditional Deletion of Endothelin cell (NCC) migration to the distal hindgut. Up to 40% of HSCR patients suffer Hirschsprung’s- Receptor-B ’ Model of Hirschsprung s Disease. PLoS associated enterocolitis (HAEC), with an incidence that is unchanged from the pre-operative ONE 10(6): e0128822. doi:10.1371/journal. pone.0128822 to the post-operative state. Recent reports indicate that signaling pathways involved in NCC migration may also be involved in the development of secondary lymphoid organs. We hy- Academic Editor: Anatoly V. Grishin, Childrens Hospital Los Angeles, UNITED STATES pothesize that gastrointestinal (GI) mucosal immune defects occur in HSCR that may contrib- ute to enterocolitis. EdnrB was deleted from the neural crest (EdnrBNCC-/-) resulting in mutants Received: November 12, 2014 with defective NCC migration, distal colonic aganglionosis and the development of enterocoli- Accepted: May 1, 2015 tis. -
University of Groningen Genetics Dissection and Functional
University of Groningen Genetics dissection and functional studies in Hirschsprung disease Sribudiani, Yunia IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2011 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Sribudiani, Y. (2011). Genetics dissection and functional studies in Hirschsprung disease Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 11-02-2018 Genetic Dissection and Functional Studies in Hirschsprung Disease Yunia Sribudiani Genetic Dissection and Functional Studies in Hirschsprung Disease Y. Sribudiani PhD Thesis – Department of Genetics University Medical Center Groningen, University of Groningen Groningen, the Netherlands This study was financially supported by University of Groningen and Research Institute GUIDE. ISBN/EAN: 978-94-6182-039-6 Cover Ilustration: Ella Elviana, www.ellasworks.blogspot.com Cover & book layout: Briyan B Hendro, www.brianos.daportfolio.com Printed by: Off Page, Amsterdam, www.offpage.nl Printing of this thesis was financially supported by: University of Groningen, GUIDE and Department of Genetics - UMCG. -
G-Protein Coupled Receptors in Lipid Rafts and Caveolae: How, When and Why Do They Go There?
325 G-protein coupled receptors in lipid rafts and caveolae: how, when and why do they go there? B Chini and M Parenti1 CNR Institute of Neuroscience, Cellular and Molecular Pharmacology Section, Milan, Italy 1Department of Experimental and Environmental Medicine and Medical Biotechnologies, University of Milano-Bicocca, Monza, Italy (Requests for offprints should be addressed to B Chini; Email: [email protected]) Abstract This review describes the advances in our understanding of the role of G-protein coupled receptor (GPCR) localisation in membrane microdomains known as lipid rafts and caveolae. The growing interest in these specialised regions is due to the recognition that they are involved in the regulation of a number of cell functions, including the fine-tuning of various signalling molecules. As a number of GPCRs have been found to be enriched in lipid rafts and/or caveolae by means of different experimental approaches, we first discuss the pitfalls and uncertainties related to the use of these different procedures. We then analyse the addressing signals that drive and/or stabilise GPCRs in lipid rafts and caveolae, and explore the role of rafts/caveolae in regulating GPCR trafficking, particularly in receptor exo- and endocytosis. Finally, we review the growing evidence that lipid rafts and caveolae participate in the regulation of GPCR signalling by affecting both signalling selectivity and coupling efficacy. Journal of Molecular Endocrinology (2004) 32, 325–338 Introduction cascade (Dykstra et al. 2001, Sedwick & Altman 2002, Werlen & Palmer 2002), unravelling the role Lipid rafts and caveolae have been found to be of rafts and caveolae in the functional regulation of involved in the regulation of various cell functions, other signalling components is still at its very including the homeostasis of cholesterol (Ikonen & beginning. -
Peripheral Regulation of Pain and Itch
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1596 Peripheral Regulation of Pain and Itch ELÍN INGIBJÖRG MAGNÚSDÓTTIR ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-513-0746-6 UPPSALA urn:nbn:se:uu:diva-392709 2019 Dissertation presented at Uppsala University to be publicly examined in A1:107a, BMC, Husargatan 3, Uppsala, Friday, 25 October 2019 at 13:00 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Professor emeritus George H. Caughey (University of California, San Francisco). Abstract Magnúsdóttir, E. I. 2019. Peripheral Regulation of Pain and Itch. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1596. 71 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0746-6. Pain and itch are diverse sensory modalities, transmitted by the somatosensory nervous system. Stimuli such as heat, cold, mechanical pain and itch can be transmitted by different neuronal populations, which show considerable overlap with regards to sensory activation. Moreover, the immune and nervous systems can be involved in extensive crosstalk in the periphery when reacting to these stimuli. With recent advances in genetic engineering, we now have the possibility to study the contribution of distinct neuron types, neurotransmitters and other mediators in vivo by using gene knock-out mice. The neuropeptide calcitonin gene-related peptide (CGRP) and the ion channel transient receptor potential cation channel subfamily V member 1 (TRPV1) have both been implicated in pain and itch transmission. In Paper I, the Cre- LoxP system was used to specifically remove CGRPα from the primary afferent population that expresses TRPV1. -
Glucagon-Like Peptide-1 and Its Class BG Protein–Coupled Receptors
1521-0081/68/4/954–1013$25.00 http://dx.doi.org/10.1124/pr.115.011395 PHARMACOLOGICAL REVIEWS Pharmacol Rev 68:954–1013, October 2016 Copyright © 2016 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: RICHARD DEQUAN YE Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes Chris de Graaf, Dan Donnelly, Denise Wootten, Jesper Lau, Patrick M. Sexton, Laurence J. Miller, Jung-Mo Ahn, Jiayu Liao, Madeleine M. Fletcher, Dehua Yang, Alastair J. H. Brown, Caihong Zhou, Jiejie Deng, and Ming-Wei Wang Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (C.d.G.); School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom (D.D.); Drug Discovery Biology Theme and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (D.W., P.M.S., M.M.F.); Protein and Peptide Chemistry, Global Research, Novo Nordisk A/S, Måløv, Denmark (J.La.); Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona (L.J.M.); Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, Texas (J.-M.A.); Department of Bioengineering, Bourns College of Engineering, University of California at Riverside, Riverside, California (J.Li.); National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (D.Y., C.Z., J.D., M.-W.W.); Heptares Therapeutics, BioPark, Welwyn Garden City, United Kingdom (A.J.H.B.); and School of Pharmacy, Fudan University, Zhangjiang High-Tech Park, Shanghai, China (M.-W.W.) Downloaded from Abstract. -
NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer
Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 11-7-2018 Decipher Mechanisms by which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer Jairo Ramos [email protected] Follow this and additional works at: https://digitalcommons.fiu.edu/etd Part of the Clinical Epidemiology Commons Recommended Citation Ramos, Jairo, "Decipher Mechanisms by which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer" (2018). FIU Electronic Theses and Dissertations. 3872. https://digitalcommons.fiu.edu/etd/3872 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida DECIPHER MECHANISMS BY WHICH NUCLEAR RESPIRATORY FACTOR ONE (NRF1) COORDINATES CHANGES IN THE TRANSCRIPTIONAL AND CHROMATIN LANDSCAPE AFFECTING DEVELOPMENT AND PROGRESSION OF INVASIVE BREAST CANCER A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in PUBLIC HEALTH by Jairo Ramos 2018 To: Dean Tomás R. Guilarte Robert Stempel College of Public Health and Social Work This dissertation, Written by Jairo Ramos, and entitled Decipher Mechanisms by Which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer, having been approved in respect to style and intellectual content, is referred to you for judgment. -
Capturing Peptide–GPCR Interactions and Their Dynamics
molecules Review Capturing Peptide–GPCR Interactions and Their Dynamics Anette Kaiser * and Irene Coin Faculty of Life Sciences, Institute of Biochemistry, Leipzig University, Brüderstr. 34, D-04103 Leipzig, Germany; [email protected] * Correspondence: [email protected] Academic Editor: Paolo Ruzza Received: 31 August 2020; Accepted: 9 October 2020; Published: 15 October 2020 Abstract: Many biological functions of peptides are mediated through G protein-coupled receptors (GPCRs). Upon ligand binding, GPCRs undergo conformational changes that facilitate the binding and activation of multiple effectors. GPCRs regulate nearly all physiological processes and are a favorite pharmacological target. In particular, drugs are sought after that elicit the recruitment of selected effectors only (biased ligands). Understanding how ligands bind to GPCRs and which conformational changes they induce is a fundamental step toward the development of more efficient and specific drugs. Moreover, it is emerging that the dynamic of the ligand–receptor interaction contributes to the specificity of both ligand recognition and effector recruitment, an aspect that is missing in structural snapshots from crystallography. We describe here biochemical and biophysical techniques to address ligand–receptor interactions in their structural and dynamic aspects, which include mutagenesis, crosslinking, spectroscopic techniques, and mass-spectrometry profiling. With a main focus on peptide receptors, we present methods to unveil the ligand–receptor contact interface and methods that address conformational changes both in the ligand and the GPCR. The presented studies highlight a wide structural heterogeneity among peptide receptors, reveal distinct structural changes occurring during ligand binding and a surprisingly high dynamics of the ligand–GPCR complexes. Keywords: GPCR activation; peptide–GPCR interactions; structural dynamics of GPCRs; peptide ligands; crosslinking; NMR; EPR 1. -
The Clinical Significance of Endothelin Receptor Type B in Hepatocellular
Experimental and Molecular Pathology 107 (2019) 141–157 Contents lists available at ScienceDirect Experimental and Molecular Pathology journal homepage: www.elsevier.com/locate/yexmp The clinical significance of endothelin receptor type B in hepatocellular T carcinoma and its potential molecular mechanism ⁎ Lu Zhanga,1, Bin Luob,1, Yi-wu Danga, Rong-quan Heb, Gang Chena, Zhi-gang Pengb, , ⁎ Zhen-bo Fenga, a Department of Pathology, First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region530021,PR China b Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi Zhuang Autonomous Region 530021, PR China ARTICLE INFO ABSTRACT Keywords: Objective: To explore the clinical significance and potential molecular mechanism of endothelin receptor typeB Endothelin receptor type B (EDNRB) in hepatocellular carcinoma (HCC). Hepatocellular carcinoma Methods: Immunohistochemistry was used to detect EDNRB protein expression level in 67 HCC paraffin em- Immunohistochemistry bedded tissues and adjacent tissues. Correlations between EDNRB expression level and clinicopathologic para- meters were analyzed in our study. The expression level and clinical significance of EDNRB in HCC were also evaluated from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The cBioPortal for Cancer Genomics was employed to analyze the EDNRB related genes, and Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Protein-Protein Interaction (PPI) network were conducted for those EDNRB related genes. Results: Lower expression level of EDNRB in HCC was verified by immunohistochemistry than adjacent tissues (P < 0.0001). The expression level of EDNRB in HCC tissues was lower than normal control liver tissues based on TCGA and GEO data (standard mean difference [SMD] = −1.48, 95% [confidence interval] CI: 2 −1.63−(−1.33), P heterogeneity = 0.116, I = 32.4%). -
New Drugs and Emerging Therapeutic Targets in the Endothelin Signaling Pathway and Prospects for Personalized Precision Medicine
Physiol. Res. 67 (Suppl. 1): S37-S54, 2018 https://doi.org/10.33549/physiolres.933872 REVIEW New Drugs and Emerging Therapeutic Targets in the Endothelin Signaling Pathway and Prospects for Personalized Precision Medicine A. P. DAVENPORT1, R. E. KUC1, C. SOUTHAN2, J. J. MAGUIRE1 1Experimental Medicine and Immunotherapeutics, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom, 2Deanery of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom Received January 26, 2018 Accepted March 29, 2018 Summary Key words During the last thirty years since the discovery of endothelin-1, Allosteric modulators • Biased signaling • G-protein coupled the therapeutic strategy that has evolved in the clinic, mainly in receptors • Endothelin-1 • Monoclonal antibodies • Pepducins • the treatment of pulmonary arterial hypertension, is to block the Single nucleotide polymorphisms action of the peptide either at the ETA subtype or both receptors using orally active small molecule antagonists. Recently, there Corresponding author has been a rapid expansion in research targeting ET receptors A. P. Davenport, Experimental Medicine and Immunotherapeutics, using chemical entities other than small molecules, particularly University of Cambridge, Addenbrooke's Hospital, Cambridge, monoclonal antibody antagonists and selective peptide agonists CB2 0QQ, United Kingdom. Fax: 01223 762576. E-mail: and antagonists. While usually sacrificing oral bio-availability, [email protected] these compounds have other therapeutic advantages with the potential to considerably expand drug targets in the endothelin Introduction pathway and extend treatment to other pathophysiological conditions. Where the small molecule approach has been During the last thirty years since the discovery retained, a novel strategy to combine two vasoconstrictor of endothelin-1 (ET-1), the therapeutic strategy that has targets, the angiotensin AT1 receptor as well as the ETA receptor evolved in the clinic, mainly in the treatment of in the dual antagonist sparsentan has been developed. -
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58 1 G S Y ONG and M J YOUNG Mineralocorticoid cell signalling 58: 1 R33–R57 Review Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways Gregory S Y Ong1,2 and Morag J Young1,3 1 Cardiovascular Endocrinology Laboratory, Centre for Endocrinology and Metabolism, Hudson Institute Correspondence of Medical Research, Clayton, Victoria, Australia should be addressed 2 Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia to M J Young 3 Department of Physiology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia Email [email protected] Abstract The mineralocorticoid receptor (MR) and mineralocorticoids regulate epithelial handling Key Words of electrolytes, and induces diverse effects on other tissues. Traditionally, the effects f aldosterone of MR were ascribed to ligand–receptor binding and activation of gene transcription. f mineralocorticoid However, the MR also utilises a number of intracellular signalling cascades, often by receptor transactivating unrelated receptors, to change cell function more rapidly. Although f glucocorticoid aldosterone is the physiological mineralocorticoid, it is not the sole ligand for MR. f MAPK pathways Tissue-selective and mineralocorticoid-specific effects are conferred through the f GPER f EGFR enzyme 11β-hydroxysteroid dehydrogenase 2, cellular redox status and properties of the MR itself. Furthermore, not all aldosterone effects are mediated via MR, with implication of the involvement of other membrane-bound receptors such as GPER. Journal of Molecular Endocrinology This review will describe the ligands, receptors and intracellular mechanisms available for mineralocorticoid hormone and receptor signalling and illustrate their complex Journal of Molecular interactions in physiology and disease. -
Endothelin B Receptor, a New Target in Cancer Immune Therapy Lana E
Molecular Pathways Endothelin B Receptor, a New Target in Cancer Immune Therapy Lana E. Kandalaft, Andrea Facciabene, Ron J. Buckanovich, and George Coukos Abstract The endothelins and their G protein-coupled receptors A and B have been implicated in numerous diseases and have recently emerged as pivotal players in a variety of malignancies. Tumors over- express the endothelin 1 (ET-1) ligand and the endothelin-A-receptor (ETAR). Their interaction induces tumor growth and metastasis by promoting tumor cell survival and proliferation, angio- genesis, and tissue remodeling. On the basis of results from xenograft models, drug development efforts have focused on antagonizing the autocrine-paracrine effects mediated by ET-1/ETAR. In this review, we discuss a novel role of the endothelin-B-receptor (ETBR) in tumorigenesis and the effect of its blockade during cancer immune therapy.We highlight key characteristics of the B re- ceptor such as its specific overexpression in the tumor compartment; and specifically, in the tu- mor endothelium, where its activation by ET-1suppressesT-cell adhesion and homing to tumors. We also review our recent findings on the effects of ETBR-specific blockade in increasingT-cell homing to tumors and enhancing the efficacy of otherwise ineffective immunotherapy. Background functions by binding to ETARandETBR on vascular endothelial cells and pericytes. Balanced activation of the two receptors The endothelin system maintains vascular tone and regulates endothelial cell prolif- The endothelin system comprises four endothelin (ET) eration (14, 15), whereas imbalance in this system contributes peptide ligands, ET-1, 2, 3 (1), and the more recently discovered to the onset of hemodynamic disorders.