Identification of Neuropeptide Receptors Expressed By
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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 ................................................................................................. -
Pipeline of Medications to Treat Substance Use Disorders
Pipeline of Medications to Treat Substance Use Disorders Iván D. Montoya, M.D., M.P.H. Clinical Director and Deputy Director Division of Therapeutics and Medical Consequences NIDA • Cocaine Outline • Methamphetamine • Cannabis Past-Year Prevalence Per 1,000 1,000 People Per NSDUH, 2018 Past-Year Prevalence Per 1,000 1,000 People Per NSDUH, 2018 Number of Overdose Deaths CDC, 2018 Molecular Neurobiology of Stimulant Use Disorders Glutamate Enkephalin or Excitatory Input Dynorphin Inhibitory Neuron k Opioid Dopamine Receptors Enkephalin Receptors Inhibitory Dopamine Neuron GABA Neuron Neuron m Opioid REWARD Receptors GABA-A Receptors GABA Inhibitory Feedback GABA Presynaptic Inhibitory Opioid Neuron Receptors (m, d?) Ventral Tegmental Area Nucleus Accumbens (VTA) (NAc) Adapted from Koop, 2016 • 5HT2c Agonist - Lorcaserin (Belviq XR®) • Orexin 1 antagonists Cocaine • EMB-101 (Oxazepam + Metyrapone) • Buprenorphine + Opioid Antagonist – Clinical Studies • Ketamine • Oxytocin • L-Tetrahydropalmatine (L-THP) 5-HT2C Agonist - Lorcaserin • Clinically available • Selective agonist • Modulate mesolimbic dopamine, decreasing dopamine release • FDA-approved for weight loss • Lorcaserin (Belviq®)10 mg bid • Lorcaserin XR (Belviq XR®) 20 mg qd • Schedule IV • Arena Pharmaceuticals - Eisai Inc. Lorcaserin Pre-clinical Studies - Stimulants • Decrease cocaine self-administration and the reinstatement of responding for cocaine (Grottick et al., 2000; Burmeister et al., 2004; Burbassi and Cervo 2008; Cunningham et al., 2011; Manvich et al., 2012; RüediBettschen -
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. -
Multiplex Gpcr Internalization Assay Using Reverse Transduction on Adenoviral Vector Immobilized Microparticles S
MULTIPLEX GPCR INTERNALIZATION ASSAY USING REVERSE TRANSDUCTION ON ADENOVIRAL VECTOR IMMOBILIZED MICROPARTICLES S. Han1,2, H.J. Bae1,2, W. Park3 and S. Kwon1,2* 1Department of Electrical and Computer Engineering, Inter-university Semiconductor Research Center (ISRC), Seoul National University, SOUTH KOREA 2Center for Nanoparticle Research, Institute for Basic Science (IBS), SOUTH KOREA and 3Department of Electronics and Radio Engineering, Institute for Laser Engineering, Kyung Hee University, SOUTH KOREA ABSTRACT We present a new multiplexing method for high-throughput cell-based assays in a microtiter well based on reverse transduction of cells by adenoviral vectors immobilized on encoded microparticles. Our particle-based approach spatially confines the gene delivery to cells seeded on the particles and provides the code for identifying the delivered gene, thus easily achieving a multiplex cell microarray in a microtiter well by means of a single pipetting without the cross- expression of genes and the positional identification. Utilizing this method with adenoviral vectors having a G-protein coupled recpeptor (GPCR) gene, we demonstrated 3-plex GPCR internalization assay. KEYWORDS: Multiplex GPCR assay, Reverse transduction, Adenovirus, Encoded microparticle INTRODUCTION G-protein coupled receptors (GPCRs) in the cell membrane are major drug targets in pharmaceutical industry since they interact with a huge variety of endogenous ligands and trigger intracellular functions related to many physiological processes or diseases [1]. Many cell-based assay strategies have been developed to identify GPCR-targeted drugs with more biologically relevant data. Since typical cell-based assays are performed in the microtiter wells and it allows only one type of receptor for each well, multiplex cellular assay technologies have emerged to run high-throughput compound screening with over several hundreds of GPCRs. -
Neurotensin Activates Gabaergic Interneurons in the Prefrontal Cortex
The Journal of Neuroscience, February 16, 2005 • 25(7):1629–1636 • 1629 Behavioral/Systems/Cognitive Neurotensin Activates GABAergic Interneurons in the Prefrontal Cortex Kimberly A. Petrie,1 Dennis Schmidt,1 Michael Bubser,1 Jim Fadel,1 Robert E. Carraway,2 and Ariel Y. Deutch1 1Departments of Pharmacology and Psychiatry, Vanderbilt University Medical Center, Nashville, Tennessee 37212, and 2Department of Physiology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655 Converging data suggest a dysfunction of prefrontal cortical GABAergic interneurons in schizophrenia. Morphological and physiological studies indicate that cortical GABA cells are modulated by a variety of afferents. The peptide transmitter neurotensin may be one such modulator of interneurons. In the rat prefrontal cortex (PFC), neurotensin is exclusively localized to dopamine axons and has been suggested to be decreased in schizophrenia. However, the effects of neurotensin on cortical interneurons are poorly understood. We used in vivo microdialysis in freely moving rats to assess whether neurotensin regulates PFC GABAergic interneurons. Intra-PFC administra- tion of neurotensin concentration-dependently increased extracellular GABA levels; this effect was impulse dependent, being blocked by treatment with tetrodotoxin. The ability of neurotensin to increase GABA levels in the PFC was also blocked by pretreatment with 2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazole-3-yl)carbonylamino]tricyclo(3.3.1.1.3.7)decan-2-carboxylic acid (SR48692), a high-affinity neurotensin receptor 1 (NTR1) antagonist. This finding is consistent with our observation that NTR1 was localized to GABAergic interneurons in the PFC, particularly parvalbumin-containing interneurons. Because neurotensin is exclusively localized to dopamine axons in the PFC, we also determined whether neurotensin plays a role in the ability of dopamine agonists to increase extracellular GABA levels. -
Novel Drug-Like Somatostatin Receptor 4 Agonists Are Potential Analgesics for Neuropathic Pain
International Journal of Molecular Sciences Article Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain 1,2, 3, 1,2 4 1,2 Boglárka Kántás y, Rita Börzsei y, Éva Sz˝oke ,Péter Bánhegyi , Ádám Horváth , 1,2 1,2 1 1,2, Ágnes Hunyady , Éva Borbély , Csaba Hetényi , Erika Pintér y and 1,2, , Zsuzsanna Helyes * y 1 Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary 2 Szentágothai Research Centre and Centre for Neuroscience, University of Pécs, Ifjúság str. 20, H-7624 Pécs, Hungary 3 Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Szigeti str. 12, H-7624 Pécs, Hungary 4 Avicor Ltd., Herman Ottó str. 15, H-1022 Budapest, Hungary * Correspondence: [email protected] These authors contributed equally to this work. y Received: 14 October 2019; Accepted: 9 December 2019; Published: 11 December 2019 Abstract: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1–C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. -
Hypothalamic Mechanisms Associated with Corticotropin-Releasing Factor- Induced Anorexia in Chicks T ⁎ Jinxin Wanga, Justin Matiasa, Elizabeth R
Neuropeptides 74 (2019) 95–102 Contents lists available at ScienceDirect Neuropeptides journal homepage: www.elsevier.com/locate/npep Hypothalamic mechanisms associated with corticotropin-releasing factor- induced anorexia in chicks T ⁎ Jinxin Wanga, Justin Matiasa, Elizabeth R. Gilberta,b, Tetsuya Tachibanac, Mark A. Clinea,b, a Department of Animal and Poultry Sciences, School of Neuroscience, USA b Virginia Polytechnic Institute and State University, Blacksburg 24061, VA, USA c Department of Agrobiological Science, Faculty of Agriculture, Ehime University, Matsuyama 790-8566, Japan ARTICLE INFO ABSTRACT Keywords: Central administration of corticotropin-releasing factor (CRF), a 41-amino acid peptide, is associated with potent Arcuate nucleus anorexigenic effects in rodents and chickens. However, the mechanism underlying this effect remains unclear. Chick Hence, the objective of the current study was to elucidate the hypothalamic mechanisms that mediate CRF- Corticotropin-releasing factor induced anorexia in 4 day-old Cobb-500 chicks. After intracerebroventricular (ICV) injection of 0.02 nmol of Hypothalamus CRF, CRF-injected chicks ate less than vehicle chicks while no effect on water intake was observed at 30 min Paraventricular nucleus post-injection. In subsequent experiments, the hypothalamus samples were processed at 60 min post-injection. The CRF-injected chicks had more c-Fos immunoreactive cells in the arcuate nucleus (ARC), dorsomedial nucleus (DMN), ventromedial hypothalamus (VMH), and paraventricular nucleus (PVN) of the hypothalamus than ve- hicle-treated chicks. CRF injection was associated with decreased whole hypothalamic mRNA abundance of neuropeptide Y receptor sub-type 1 (NPYR1). In the ARC, CRF-injected chicks expressed more CRF and CRF receptor sub-type 2 (CRFR2) mRNA but less agouti-related peptide (AgRP), NPY, and NPYR1 mRNA than ve- hicle-injected chicks. -
Mutant Neuropeptide S Receptor Reduces Sleep Duration with Preserved Memory Consolidation Lijuan Xing, Guangsen Shi, Yulia Mostovoy, Nicholas W
SCIENCE TRANSLATIONAL MEDICINE | RESEARCH ARTICLE SLEEP Copyright © 2019 The Authors, some rights reserved; Mutant neuropeptide S receptor reduces sleep duration exclusive licensee American Association with preserved memory consolidation for the Advancement Lijuan Xing1*, Guangsen Shi1*, Yulia Mostovoy2, Nicholas W. Gentry1, Zenghua Fan1, of Science. No claim 1 2,3,4 5 1,4,6,7† 1,4,6,7† to original U.S. Thomas B. Mcmahon , Pui-Yan Kwok , Christopher R. Jones , Louis J. Ptáček , Ying-Hui Fu Government Works Sleep is a crucial physiological process for our survival and cognitive performance, yet the factors controlling hu- man sleep regulation remain poorly understood. Here, we identified a missense mutation in a G protein–coupled neuropeptide S receptor 1 (NPSR1) that is associated with a natural short sleep phenotype in humans. Mice carry- ing the homologous mutation exhibited less sleep time despite increased sleep pressure. These animals were also resistant to contextual memory deficits associated with sleep deprivation. In vivo, the mutant receptors showed Downloaded from increased sensitivity to neuropeptide S exogenous activation. These results suggest that the NPS/NPSR1 pathway might play a critical role in regulating human sleep duration and in the link between sleep homeostasis and mem- ory consolidation. INTRODUCTION In this study, we identified another FNSS family and report a http://stm.sciencemag.org/ Sleep remains a relatively understudied phenomenon, despite being mutation in the NPSR1 gene causing a short sleep phenotype. Neu- essential in some form to most vertebrate life. Although humans ropeptide S receptor 1 (NPSR1) is a G protein–coupled receptor spend about one-third of their lives in the sleep state, an under- whose cognate ligand, neuropeptide S (NPS), has been reported to standing and recognition of its importance for our well-being are modulate arousal and sleep behaviors (17). -
Procedure Guideline for Somatostatin Receptor Scintigraphy with 111In-Pentetreotide
PROCEDURE GUIDELINES Procedure Guideline for Somatostatin Receptor Scintigraphy with 111In-Pentetreotide Helena R. Balon, Stanley J. Goldsmith, Barry A. Siegel, Edward B. Silberstein, Eric P. Krenning, Otto Lang, and Kevin J. Donohoe William Beaumont Hospital, Royal Oak, Michigan; New York Hospital–Cornell Medical, New York, NY; Mallinckrodt Institute of Radiology, St. Louis, Missouri; University of Cincinnati Medical Center, Cincinnati, Ohio; Beth Israel Deaconess Medical Center, Boston, Massachusetts; University Hospital Dijkzigt, Rotterdam, The Netherlands; and Third Medical School, Charles University, Prague, Czech Republic ● Paraganglioma. Key Words: guideline; octreotide; somatostatin receptor ● Pituitary adenomas. J Nucl Med 2001; 42:1134–1138 ● Small cell lung carcinoma. Other tumors and disease processes may also be detected by 111In-pentetreotide scintigraphy and knowledge of the PART I: PURPOSE patient’s history is thus important. These disorders may The purpose of this guideline is to assist nuclear medicine include, but are not limited to, the following: practitioners in recommending, performing, interpreting, and reporting the results of somatostatin receptor scintigra- ● Astrocytomas. phy with 111In-pentetreotide. ● Benign and malignant bone tumors. ● Breast carcinoma. PART II: BACKGROUND INFORMATION AND ● Differentiated thyroid carcinoma (papillary, follicular, DEFINITIONS and Hu¨rthle cell). 111In-pentetreotide is a [111In-DTPA-D-Phe-] conjugate of ● Lymphoma (Hodgkin’s and non-Hodgkin’s). octreotide, a somatostatin analog -
Discovery of an Ancient Role As Muscle Relaxants
Original citation: Cai, Weigang, Kim, Chan-Hee, Go, Hye-Jin, Egertová, Michaela, Zampronio, Cleidiane, Jones, Alexandra M., Park, Nam Gyu and Elphick, Maurice R. (2018) Biochemical, anatomical, and pharmacological characterization of calcitonin-type neuropeptides in starfish : discovery of an ancient role as muscle relaxants. Frontiers in Neuroscience, 12 . 382. doi:10.3389/fnins.2018.00382 Permanent WRAP URL: http://wrap.warwick.ac.uk/103092 Copyright and reuse: The Warwick Research Archive Portal (WRAP) makes this work of researchers of the University of Warwick available open access under the following conditions. This article is made available under the Creative Commons Attribution 4.0 International license (CC BY 4.0) and may be reused according to the conditions of the license. For more details see: http://creativecommons.org/licenses/by/4.0/ A note on versions: The version presented in WRAP is the published version, or, version of record, and may be cited as it appears here. For more information, please contact the WRAP Team at: [email protected] warwick.ac.uk/lib-publications ORIGINAL RESEARCH published: 08 June 2018 doi: 10.3389/fnins.2018.00382 Biochemical, Anatomical, and Pharmacological Characterization of Calcitonin-Type Neuropeptides in Starfish: Discovery of an Ancient Role as Muscle Relaxants Weigang Cai 1, Chan-Hee Kim 2, Hye-Jin Go 2, Michaela Egertová 1, Cleidiane G. Zampronio 3, Alexandra M. Jones 3, Nam Gyu Park 2* and Maurice R. Elphick 1* 1 School of Biological & Chemical Sciences, Queen Mary University of London, London, United Kingdom, 2 Department of Biotechnology, College of Fisheries Sciences, Pukyong National University, Busan, South Korea, 3 School of Life Sciences and Proteomics Research Technology Platform, University of Warwick, Coventry, United Kingdom Calcitonin (CT) is a peptide hormone released by the thyroid gland that regulates blood Ca2+ levels in mammals. -
Conformational Dynamics Between Transmembrane Domains And
RESEARCH ARTICLE Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor Vanessa A Gutzeit1, Jordana Thibado2, Daniel Starer Stor2, Zhou Zhou3, Scott C Blanchard2,3,4, Olaf S Andersen2,3, Joshua Levitz2,4,5* 1Neuroscience Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States; 2Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States; 3Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States; 4Tri-Institutional PhD Program in Chemical Biology, New York, United States; 5Department of Biochemistry, Weill Cornell Medicine, New York, United States Abstract Metabotropic glutamate receptors (mGluRs) are class C, synaptic G-protein-coupled receptors (GPCRs) that contain large extracellular ligand binding domains (LBDs) and form constitutive dimers. Despite the existence of a detailed picture of inter-LBD conformational dynamics and structural snapshots of both isolated domains and full-length receptors, it remains unclear how mGluR activation proceeds at the level of the transmembrane domains (TMDs) and how TMD-targeting allosteric drugs exert their effects. Here, we use time-resolved functional and conformational assays to dissect the mechanisms by which allosteric drugs activate and modulate mGluR2. Single-molecule subunit counting and inter-TMD fluorescence resonance energy transfer *For correspondence: measurements in living cells -
Neurotransmitter and Neuropeptide Regulation of Mast Cell Function
Xu et al. Journal of Neuroinflammation (2020) 17:356 https://doi.org/10.1186/s12974-020-02029-3 REVIEW Open Access Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review Huaping Xu1, Xiaoyun Shi2, Xin Li3, Jiexin Zou4, Chunyan Zhou5, Wenfeng Liu5, Huming Shao5, Hongbing Chen5 and Linbo Shi4* Abstract The existence of the neural control of mast cell functions has long been proposed. Mast cells (MCs) are localized in association with the peripheral nervous system (PNS) and the brain, where they are closely aligned, anatomically and functionally, with neurons and neuronal processes throughout the body. They express receptors for and are regulated by various neurotransmitters, neuropeptides, and other neuromodulators. Consequently, modulation provided by these neurotransmitters and neuromodulators allows neural control of MC functions and involvement in the pathogenesis of mast cell–related disease states. Recently, the roles of individual neurotransmitters and neuropeptides in regulating mast cell actions have been investigated extensively. This review offers a systematic review of recent advances in our understanding of the contributions of neurotransmitters and neuropeptides to mast cell activation and the pathological implications of this regulation on mast cell–related disease states, though the full extent to which such control influences health and disease is still unclear, and a complete understanding of the mechanisms underlying the control is lacking. Future validation of animal and in vitro models also is needed, which incorporates the integration of microenvironment-specific influences and the complex, multifaceted cross-talk between mast cells and various neural signals. Moreover, new biological agents directed against neurotransmitter receptors on mast cells that can be used for therapeutic intervention need to be more specific, which will reduce their ability to support inflammatory responses and enhance their potential roles in protecting against mast cell–related pathogenesis.