Secretin and Autism: a Clue but Not a Cure
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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. -
The Role of Clinical Proteomics, Lipidomics, and Genomics in the Diagnosis of Alzheimer's Disease
Edith Cowan University Research Online ECU Publications Post 2013 3-31-2016 The Role of Clinical Proteomics, Lipidomics, and Genomics in the Diagnosis of Alzheimer's Disease Ian James Martins Edith Cowan University Follow this and additional works at: https://ro.ecu.edu.au/ecuworkspost2013 Part of the Medicine and Health Sciences Commons 10.3390/proteomes4020014 Martins, I. J. (2016). The Role of Clinical Proteomics, Lipidomics, and Genomics in the Diagnosis of Alzheimer’s Disease. Proteomes, 4(2), 14.Available here This Journal Article is posted at Research Online. https://ro.ecu.edu.au/ecuworkspost2013/2456 proteomes Article The Role of Clinical Proteomics, Lipidomics, and Genomics in the Diagnosis of Alzheimer’s Disease Ian James Martins School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup 6027, Australia; [email protected]; Tel.: +61-8-6304-2574 Academic Editors: Edwin Lasonder and Jacek R. Wisniewski Received: 5 February 2016; Accepted: 28 March 2016; Published: 31 March 2016 Abstract: The early diagnosis of Alzheimer’s disease (AD) has become important to the reversal and treatment of neurodegeneration, which may be relevant to premature brain aging that is associated with chronic disease progression. Clinical proteomics allows the detection of various proteins in fluids such as the urine, plasma, and cerebrospinal fluid for the diagnosis of AD. Interest in lipidomics has accelerated with plasma testing for various lipid biomarkers that may with clinical proteomics provide a more reproducible diagnosis for early brain aging that is connected to other chronic diseases. The combination of proteomics with lipidomics may decrease the biological variability between studies and provide reproducible results that detect a community’s susceptibility to AD. -
Cloning, Characterization, and Expression of a Human Calcitonin Receptor from an Ovarian Carcinoma Cell Line
Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line. A H Gorn, … , S M Krane, S R Goldring J Clin Invest. 1992;90(5):1726-1735. https://doi.org/10.1172/JCI116046. Research Article A human ovarian small cell carcinoma line (BIN-67) expresses abundant calcitonin (CT) receptors (CTR) (143,000 per cell) that are coupled, to adenylate cyclase. The dissociation constants (Kd) for the CTRs on these BIN-67 cells is approximately 0.42 nM for salmon CT and approximately 4.6 nM for human CT. To clone a human CTR (hCTR), a BIN-67 cDNA library was screened using a cDNA probe from a porcine renal CTR (pCTR) that we recently cloned. One positive clone of 3,588 bp was identified. Transfection of this cDNA into COS cells resulted in expression of receptors with high affinity for salmon CT (Kd = approximately 0.44 nM) and for human CT (Kd = approximately 5.4 nM). The expressed hCTR was coupled to adenylate cyclase. Northern analysis with the hCTR cDNA probe indicated a single transcript of approximately 4.2 kb. The cloned cDNA encodes a putative peptide of 490 amino acids with seven potential transmembrane domains. The amino acid sequence of the hCTR is 73% identical to the pCTR, although the hCTR contains an insert of 16 amino acids between transmembrane domain I and II. The structural differences may account for observed differences in binding affinity between the porcine renal and human ovarian CTRs. The CTRs are closely related to the receptors for parathyroid hormone-parathyroid hormone-related peptide and secretin; these receptors comprise a […] Find the latest version: https://jci.me/116046/pdf Cloning, Characterization, and Expression of a Human Calcitonin Receptor from an Ovarian Carcinoma Cell Line Alan H. -
Human Physiology Course
Human Physiology Course Endocrine System Principles of hormonal regulation Assoc. Prof. Mária Pallayová, MD, PhD [email protected] Department of Human Physiology, PJ Safarik University FOM April 6-7, 2020 (9th week – Summer Semester 2019/2020) Chemical messenger systems Types of chemical messenger systems: Neurotransmitters Endocrine hormones Neuroendocrine hormones Paracrines Autocrines Cytokines Neurotransmitters are released by axon terminals of neurons into the synaptic junctions act locally to control nerve cell functions. Endocrine hormones are released by glands or specialized cells into the circulating blood influence the function of target cells at another location in the body. Neuroendocrine hormones are secreted by neurons into the circulating blood influence the function of target cells at another location in the body. Paracrines are secreted by cells into the extracellular fluid affect neighboring target cells of a different type. Autocrines are secreted by cells into the extracellular fluid affect the function of the same cells that produced them. Cytokines are peptides secreted by cells into the extracelular fluid can function as autocrines, paracrines, or endocrine hormones. e.g., the interleukins and other lymphokines secreted by helper cells and act on other cells of the immune system. adipokines= cytokine hormones (e.g., leptin) produced by adipocytes. Hormonal vs. Humoral ????? Hormonal vs. Humoral hormonal = endocrine humoral = endocrine + autocrine + paracrine The Endocrine Sytem the endocrine signaling communication and coordination system. relies on hormones, chemical substances that are released into the bloodstream, to deliver messages to cells of the body. Hormones and Functions Hormones are produced by: – endocrine glands – endocrine tissues (the brain, heart, kidney, adipose tissue, and GI tract). -
International Union of Pharmacology. XXXV. the Glucagon Receptor Family
0031-6997/03/5501-167–194$7.00 PHARMACOLOGICAL REVIEWS Vol. 55, No. 1 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 30106/1047548 Pharmacol Rev 55:167–194, 2003 Printed in U.S.A International Union of Pharmacology. XXXV. The Glucagon Receptor Family KELLY E. MAYO, LAURENCE J. MILLER, DOMINIQUE BATAILLE, STEPHANE´ DALLE, BURKHARD GO¨ KE, BERNARD THORENS, AND DANIEL J. DRUCKER Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, Evanston, Illinois (K.E.M.); Mayo Clinic and Foundation, Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, Minnesota (L.J.M.); INSERM U 376, Montpellier, France (D.B., S.D.); Department of Medicine II, Grosshadern, Klinikum der Ludwig-Maximilians, University of Munich, Germany (B.G.); Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland (B.T.); and Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada (D.J.D.) Abstract .............................................................................. 168 I. Introduction ........................................................................... 168 II. Secretin receptor....................................................................... 169 A. Molecular basis for receptor nomenclature ............................................ 169 B. Endogenous agonist................................................................. 169 C. Receptor structure ................................................................. -
Constitutive Activation of G Protein-Coupled Receptors and Diseases: Insights Into Mechanisms of Activation and Therapeutics
Pharmacology & Therapeutics 120 (2008) 129–148 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: S. Enna Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics Ya-Xiong Tao ⁎ Department of Anatomy, Physiology and Pharmacology, 212 Greene Hall, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA article info abstract The existence of constitutive activity for G protein-coupled receptors (GPCRs) was first described in 1980s. In Keywords: 1991, the first naturally occurring constitutively active mutations in GPCRs that cause diseases were reported G protein-coupled receptor Disease in rhodopsin. Since then, numerous constitutively active mutations that cause human diseases were reported Constitutively active mutation in several additional receptors. More recently, loss of constitutive activity was postulated to also cause Inverse agonist diseases. Animal models expressing some of these mutants confirmed the roles of these mutations in the Mechanism of activation pathogenesis of the diseases. Detailed functional studies of these naturally occurring mutations, combined Transgenic model with homology modeling using rhodopsin crystal structure as the template, lead to important insights into the mechanism of activation in the absence of crystal structure of GPCRs in active state. Search for inverse Abbreviations: agonists on these receptors will be critical for correcting the diseases cause by activating mutations in GPCRs. ADRP, autosomal dominant retinitis pigmentosa Theoretically, these inverse agonists are better therapeutics than neutral antagonists in treating genetic AgRP, Agouti-related protein AR, adrenergic receptor diseases caused by constitutively activating mutations in GPCRs. CAM, constitutively active mutant © 2008 Elsevier Inc. -
Glucagon and Gastrointestinal Motility in Relation to Thyroid-Parathyroid Function
Upsala J Med Sci 77: 183-188, 1972 Glucagon and Gastrointestinal Motility in Relation to Thyroid-Parathyroid Function HENRY JOHANSSON and ANDERS SEGERSTROM From the Department of Surgery, University Hospital, Uppsala, Sweden ABSTRACT MATERIAL Gastrointestinal propulsive motility was studied after The material consisted of 109 male albino rats (Sprague- inhgastric deposition of a non-absorbable isotope in Dawley) fed on laboratory food and with free access to rats after subcutaneous glucagon injections. Glucagon water. The animals were distributed at random in fol- administration was followed by retardation of gastric lowing series: emptying. The results indicated that the retarding effect Series I of glucagon on gastrointestinal propulsion was independent The influence of glucagon on gastrointestinal motility in of the presence of both thyroid and parathyroid tissue. intact rats. The observation period was 7 days. The hypocalcemic effect of glucagon was exerted in- dependently of the presence of thyroid tissue, Le. thyro- 1. Intact rats given 1.2 mg glucagon/kg body weight calcitonin. (GN-A, n= 6) 2. Intact rats given 4.8 mg glucagon/kg body weight (GN-B, n= 5) 3. Intact rats given 9.6 mg glucagon/kg body weight INTRODUCTION (GN-C, n= 12) 4. Intact rats given glucine buffert (GLY, n= 10). Glucagon is known to influence gastrointestinal Series I1 motility. In man, Dotevall & Kock (2) observed The influence of glucagon on gastrointestinal motility in that glucagon retarded gastrointestinal motility parathyroidectomized rats. The animals were given 4.8 independently of the hyperglucemia. In dogs, mg glucagon/kg body weight. The observation period glucagon retarded motility of the stomach ani was 90 days. -
Insights Into Nuclear G-Protein-Coupled Receptors As Therapeutic Targets in Non-Communicable Diseases
pharmaceuticals Review Insights into Nuclear G-Protein-Coupled Receptors as Therapeutic Targets in Non-Communicable Diseases Salomé Gonçalves-Monteiro 1,2, Rita Ribeiro-Oliveira 1,2, Maria Sofia Vieira-Rocha 1,2, Martin Vojtek 1,2 , Joana B. Sousa 1,2,* and Carmen Diniz 1,2,* 1 Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal; [email protected] (S.G.-M.); [email protected] (R.R.-O.); [email protected] (M.S.V.-R.); [email protected] (M.V.) 2 LAQV/REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal * Correspondence: [email protected] (J.B.S.); [email protected] (C.D.) Abstract: G-protein-coupled receptors (GPCRs) comprise a large protein superfamily divided into six classes, rhodopsin-like (A), secretin receptor family (B), metabotropic glutamate (C), fungal mating pheromone receptors (D), cyclic AMP receptors (E) and frizzled (F). Until recently, GPCRs signaling was thought to emanate exclusively from the plasma membrane as a response to extracellular stimuli but several studies have challenged this view demonstrating that GPCRs can be present in intracellular localizations, including in the nuclei. A renewed interest in GPCR receptors’ superfamily emerged and intensive research occurred over recent decades, particularly regarding class A GPCRs, but some class B and C have also been explored. Nuclear GPCRs proved to be functional and capable of triggering identical and/or distinct signaling pathways associated with their counterparts on the cell surface bringing new insights into the relevance of nuclear GPCRs and highlighting the Citation: Gonçalves-Monteiro, S.; nucleus as an autonomous signaling organelle (triggered by GPCRs). -
AVP-Induced Counter-Regulatory Glucagon Is Diminished in Type 1 Diabetes
bioRxiv preprint doi: https://doi.org/10.1101/2020.01.30.927426; this version posted January 31, 2020. 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 4.0 International license. AVP-induced counter-regulatory glucagon is diminished in type 1 diabetes Angela Kim1,2, Jakob G. Knudsen3,4, Joseph C. Madara1, Anna Benrick5, Thomas Hill3, Lina Abdul Kadir3, Joely A. Kellard3, Lisa Mellander5, Caroline Miranda5, Haopeng Lin6, Timothy James7, Kinga Suba8, Aliya F. Spigelman6, Yanling Wu5, Patrick E. MacDonald6, Ingrid Wernstedt Asterholm5, Tore Magnussen9, Mikkel Christensen9,10,11, Tina Vilsboll9,10,12, Victoria Salem8, Filip K. Knop9,10,12,13, Patrik Rorsman3,5, Bradford B. Lowell1,2, Linford J.B. Briant3,14,* Affiliations 1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. 2Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. 3Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX4 7LE, UK. 4Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen. 5Institute of Neuroscience and Physiology, Metabolic Research Unit, University of Göteborg, 405 30, Göteborg, Sweden. 6Alberta Diabetes Institute, 6-126 Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, T6G 2E1, Canada. 7Department of Clinical Biochemistry, John Radcliffe, Oxford NHS Trust, OX3 9DU, Oxford, UK. 8Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, W12 0NN, UK. -
Localization of Glucokinase Gene Expression in the Rat Brain Ronald M
Localization of Glucokinase Gene Expression in the Rat Brain Ronald M. Lynch, Linda S. Tompkins, Heddwen L. Brooks, Ambrose A. Dunn-Meynell, and Barry E. Levin The brain contains a subpopulation of glucosensing neu- rons that alter their firing rate in response to elevated glucose concentrations. In pancreatic -cells, gluco- ammalian feeding behavior and general energy kinase (GK), the rate-limiting enzyme in glycolysis, medi- homeostasis appear to be regulated by circu- ates glucose-induced insulin release by regulating intra- lating levels of nutrients (glucose) and pep- cellular ATP production. A similar role for GK is pro- tides (e.g., leptin, insulin). Sensors to detect lev- posed to underlie neuronal glucosensing. Via in situ M els of these factors have been found to reside within specific hybridization, GK mRNA was localized to hypothalamic areas that are thought to contain relatively large popu- nuclei of the hypothalamus (1–8), where central regulation of lations of glucosensing neurons (the arcuate, ventrome- energy homeostasis is believed to be coordinated. For exam- dial, dorsomedial, and paraventricular nuclei and the lat- ple, large changes in blood glucose are correlated with cen- eral area). GK also was found in brain areas without trally mediated responses such as thermogenesis through known glucosensing neurons (the lateral habenula, the activation of the sympathetic nervous system. These changes bed nucleus stria terminalis, the inferior olive, the are monitored by the brain (9–11), and such responses are retrochiasmatic and medial preoptic areas, and the thal- altered in obesity-prone animals (11–13). Moreover, lesions amic posterior paraventricular, interpeduncular, oculo- of the ventromedial hypothalamus (VMH) prevent the hypo- motor, and anterior olfactory nuclei). -
And Oxytocin-Induced Glucagon Secretion in V1b Vasopressin Receptor Knockout Mice
361 Mutual regulation of vasopressin- and oxytocin-induced glucagon secretion in V1b vasopressin receptor knockout mice Yoko Fujiwara, Masami Hiroyama, Atsushi Sanbe, Junji Yamauchi, Gozoh Tsujimoto1 and Akito Tanoue Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan 1Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan (Requests for offprints should be addressed to A Tanoue; Email: [email protected]) Abstract [Arg8]-vasopressin (AVP) and oxytocin (OT) are neurohy- CL-14-26 further inhibited AVP- and OT-induced glucagon pophysial hormones which exert various actions, including secretions in islets of V1bRC/C mice (57 and 69% of the the control of blood glucose, in some peripheral tissues. To stimulation values respectively). In addition, both AVP and investigate the type of receptors involved in AVP- and OT stimulated glucagon secretion with the same efficacy in OT-induced glucagon secretion, we investigated the effect V1bRK/K mice as in V1bRC/C mice. AVP- and of these peptides on glucagon secretion in islets of OT-induced glucagon secretion in V1bRK/K mice was wild-type (V1bRC/C) and vasopressin V1b receptor significantly inhibited by CL-14-26. These results demonstrate knockout (V1bRK/K) mice. AVP-induced glucagon that V1b receptors can mediate OT-induced glucagon secretion secretion was significantly inhibited by the selective V1b and OTreceptors can mediate AVP-induced glucagon secretion receptor antagonist, SSR149415 (30%), and OT-induced in islets from V1bRC/C mice in the presence of a heterologous glucagon secretion by the specific OT receptor antagonist, antagonist, while AVP and OT can stimulate glucagon secretion ð Þ ½ ð Þ2; 4; 9 d CH2 5 Tyr Me Thr Tyr-NH2 OVT (CL-14-26) through the OTreceptors in V1bRK/K mice, suggesting that C C (45%), in islets of V1bR / mice. -
RT² Profiler PCR Array (96-Well Format and 384-Well [4 X 96] Format)
RT² Profiler PCR Array (96-Well Format and 384-Well [4 x 96] Format) Human GPCR Signaling PathwayFinder Cat. no. 330231 PAHS-071ZA For pathway expression analysis Format For use with the following real-time cyclers RT² Profiler PCR Array, Applied Biosystems® models 5700, 7000, 7300, 7500, Format A 7700, 7900HT, ViiA™ 7 (96-well block); Bio-Rad® models iCycler®, iQ™5, MyiQ™, MyiQ2; Bio-Rad/MJ Research Chromo4™; Eppendorf® Mastercycler® ep realplex models 2, 2s, 4, 4s; Stratagene® models Mx3005P®, Mx3000P®; Takara TP-800 RT² Profiler PCR Array, Applied Biosystems models 7500 (Fast block), 7900HT (Fast Format C block), StepOnePlus™, ViiA 7 (Fast block) RT² Profiler PCR Array, Bio-Rad CFX96™; Bio-Rad/MJ Research models DNA Format D Engine Opticon®, DNA Engine Opticon 2; Stratagene Mx4000® RT² Profiler PCR Array, Applied Biosystems models 7900HT (384-well block), ViiA 7 Format E (384-well block); Bio-Rad CFX384™ RT² Profiler PCR Array, Roche® LightCycler® 480 (96-well block) Format F RT² Profiler PCR Array, Roche LightCycler 480 (384-well block) Format G RT² Profiler PCR Array, Fluidigm® BioMark™ Format H Sample & Assay Technologies Description The Human G-Protein-Coupled Receptor Signaling PathwayFinder RT² Profiler PCR Array profiles the expression of 84 genes representative of and involved in GPCR-mediated signal transduction pathways. G-protein Coupled Receptors (GPCRs) that are represented on this array include bioactive lipid receptors, metabotropic glutamate receptors (mGluRs), GABA-B-like receptors, rhodopsin-like receptors, and secretin-like receptors. Members of the intricate network of intracellular signaling pathways involved in GPCR-mediated signal transduction are also represented on this array including the cAMP / PKA Pathway, Calcium / PKC Pathway, Calcium / NFAT Pathway, PLC Pathway, Protein Tyrosine Kinase Pathway, PKC / MEK Pathway, p43 / p44MAP Pathway, p38 MAP Pathway, PI-3 Kinase Pathway, NO-cGMP Pathway, Rho Pathway, NFκB Pathway and Jak / Stat Pathway.